EP3947352A1 - Komplementmodulatoren und verfahren dafür - Google Patents

Komplementmodulatoren und verfahren dafür

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Publication number
EP3947352A1
EP3947352A1 EP20721008.9A EP20721008A EP3947352A1 EP 3947352 A1 EP3947352 A1 EP 3947352A1 EP 20721008 A EP20721008 A EP 20721008A EP 3947352 A1 EP3947352 A1 EP 3947352A1
Authority
EP
European Patent Office
Prior art keywords
c5inh
group
alkyl
compound
complement
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20721008.9A
Other languages
English (en)
French (fr)
Inventor
Willmen Wing-Menn YOUNGSAYE
Bolin Geng
Michael R. Hale
Vincent P. Galullo
Jayashree G. Tikhe
Timothy Ryan SIEGERT
Alonso RICARDO
Derek M. LAPLACA
Douangsone D. VADYSIRISACK
Guo-Qing Tang
Kathleen Seyb
Michelle Denise HOARTY
Jonathan C. BLAIN
Joseph R. Stringer
Yongjin GONG
Claudio Sturino
Shawn GALLAGHER-DUVAL
Colin DINER
Burcin AKGUN
Qing Cao
Douglas A. Treco
Vaishnavi RAJAGOPAL
Ketki Ashok DHAMNASKAR
Zhong MA
Susan Ashwell
Jennifer DAVOREN
Xiaorong LIU
Camil SAYEGH
Wenqing Xu
Alex LEMIRE
Audrey BELOUIN
Alexandria JEANNERET
Andrew HILDERING
Barbara Bertani
Fabrizio Micheli
Bernardo Pezzati
Alfonso Pozzan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
RA Pharmaceuticals Inc
Original Assignee
RA Pharmaceuticals Inc
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Filing date
Publication date
Application filed by RA Pharmaceuticals Inc filed Critical RA Pharmaceuticals Inc
Publication of EP3947352A1 publication Critical patent/EP3947352A1/de
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the vertebrate immune response is comprised of adaptive and innate immune components. While the adaptive immune response is selective for particular pathogens and is slow to respond, components of the innate immune response recognize a broad range of pathogens and respond rapidly upon infection.
  • One such component of the innate immune response is the complement system.
  • the complement system includes about 20 circulating proteins, synthesized primarily by the liver. Components of this particular immune response were first termed “complement” due to the observation that they complemented the antibody response in the destruction of bacteria. These proteins remain in an inactive form prior to activation in response to infection. Activation occurs by way of a pathway of proteolytic cleavage initiated by pathogen recognition and leading to pathogen destruction. Three such pathways are known in the complement system and are referred to as the classical pathway, the lectin pathway, and the alternative pathway. The classical pathway is activated when an IgG or IgM molecule binds to the surface of a pathogen.
  • the lectin pathway is initiated by the mannan- binding lectin protein recognizing the sugar residues of a bacterial cell wall.
  • the alternative pathway remains active at low levels in the absence of any specific stimuli. While all three pathways differ with regard to initiating events, all three pathways converge with the cleavage of complement component C3.
  • C3 is cleaved into two products termed C3a and C3b. Of these, C3b becomes covalently linked to the pathogen surface while C3a acts as a diffusible signal to promote inflammation and recruit circulating immune cells.
  • Surface- associated C3b forms a complex with other components to initiate a cascade of reactions among the later components of the complement system. Due to the requirement for surface attachment, complement activity remains localized and minimizes destruction to non-target cells.
  • Pathogen-associated C3b facilitates pathogen destruction in two ways.
  • C3b is recognized directly by phagocytic cells and leads to engulfment of the pathogen.
  • pathogen-associated C3b initiates the formation of the membrane attack complex (MAC).
  • MAC membrane attack complex
  • C3b complexes with other complement components to form the C5-convertase complex.
  • C5-convertase formed as the result of the classical complement pathway comprises C4b and C2a in addition to C3b.
  • C5-convertase comprises two subunits of C3b as well as one Bb component.
  • Complement component C5 is cleaved by either C5-convertase complex into C5a and C5b.
  • C5a much like C3a, diffuses into the circulation and promotes inflammation, acting as a chemoattractant for inflammatory cells.
  • C5b remains attached to the cell surface where it triggers the formation of the MAC through interactions with C6, C7, C8 and C9.
  • the MAC is a hydrophilic pore that spans the membrane and promotes the free flow of fluid into and out of the cell, thereby destroying it.
  • An important component of all immune activity is the ability of the immune system to distinguish between self and non-self cells. Pathologies arise when the immune system is unable to make this distinction.
  • vertebrate cells express proteins that protect them from the effects of the complement cascade. This ensures that targets of the complement system are limited to pathogenic cells.
  • Many complement-related disorders and diseases are associated with abnormal destruction of self cells by the complement cascade.
  • subjects suffering from paroxysmal nocturnal hemoglobinuria (PNH) are unable to synthesize functional versions of the complement regulatory proteins CD55 and CD59 on hematopoietic stem cells. This results in complement-mediated hemolysis and a variety of downstream complications.
  • Other complement-related disorders and diseases include, but are not limited to: autoimmune diseases and disorders; neurological diseases and disorders; blood diseases and disorders; and infectious diseases and disorders. Experimental evidence suggests that many complement- related disorders are alleviated through inhibition of complement activity.
  • the present disclosure provides a compound having a structure of Formula (700):
  • R3 and R4 may be independently an alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl is optionally substituted; R11 may be H or an alkyl group, wherein the alkyl group is optionally substituted; R12 may be H, an alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, heteroaryl, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl group, or hetero multicyclic alkyl group, wherein the alkyl, alkenyl, alkynyl, halogen, hydroxyl, al
  • the present disclosure provides a compound having a structure of Formula (701):
  • R11 may be H or a methyl group
  • R13 may be H, halogen, -CN, -CF3, or a C 1 -C 3 alkyl group
  • R15 and R16 may be independently a H, alkyl, aryl, heteroaryl, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl group, or hetero multicyclic alkyl group, wherein the alkyl, aryl, heteroaryl group, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl, or hetero multicyclic alkyl group is optionally substituted, wherein R15 and R16, together with the nitrogen they are attached to, optionally form a 3 to 8 membered heterocyclic group, wherein the heterocyclic group may be optionally substituted;
  • R17 may be a halogen, an alkyl group, or an alkoxyl group;
  • Z D may be N or CH.
  • R15 and R16 may both be C 1 -C 3
  • R15 and R16 may be methyl groups.
  • R15 and R16, together with the nitrogen they are attached to, may form a 6-membered non-aromatic heterocyclic group.
  • R17 is an alkyl group, wherein the alkyl group is optionally substituted.
  • R17 may be an alkyl group substituted with an amine group.
  • the present disclosure provides a compound having a structure of Formula (IIe):
  • X1 may be CH or N
  • R1 may be H, a halogen, -CN, -CF3, or a C 1 -C 3 alkyl group, wherein the halogen is optionally selected from the group consisting of Cl, F, Br and I
  • R2 and R3 may be independently a H, alkyl, aryl, heteroaryl, cyclic alkyl, heterocyclic alkyl, a multicyclic alkyl group, or a hetero multicyclic alkyl group, wherein the alkyl, aryl, heteroaryl group, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl, or hetero multicyclic alkyl is optionally substituted, wherein R2 and R3, together with the nitrogen they are attached, optionally form a 3 to 8 membered heterocyclic group, wherein the heterocyclic group is optionally substituted; and R4 may be H or a C 1 -C 3 alkyl group.
  • R2 and R3 may be both C 1 -C 3 alkyl groups.
  • R4 may be H.
  • the compound may be selected from the group consisting of CU0025, CU0028, CU0029, CU0030, CU0031, CU0035, CU0043, CU0046, CU0048, CU0049, CU0050, CU0051, CU0053, CU0056, CU0057, CU0060, CU0062, CU0231, CU0232, CU0235, CU0239, CU0243, CU0244, CU0245, CU0246, CU0247, CU0255, CU0257, CU0258, CU0260, CU0261, CU0504, CU0506, CU0508, CU0509, CU0510, CU0518, CU0519, CU0521, CU0526, CU0528, CU0529, CU0533
  • the present disclosure provides a compound having a structure of Formula (IIf):
  • X1 may be CH or N
  • R1 may be H, a halogen, -CN, -CF3, or a C 1 -C 3 alkyl group, wherein the halogen is optionally selected from the group consisting of Cl, F, Br and I
  • R2 and R3 may be independently an alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl is optionally substituted
  • R4 may be H or a C 1 -C 3 alkyl group.
  • R2 and R3 may both be alkoxyl groups.
  • R2 may be -OCH3.
  • R4 may be H.
  • the compound may be selected from the group consisting of CU0025, CU0026,CU0027, CU0035, CU0036, CU0231, CU0232, CU0252, CU0253, CU0256, CU0258, CU0259, CU0261, CU0262, CU0508, CU0515, CU0516, CU0532, CU0535, CU0543, CU0582, CU0591, CU0595, CU0602, CU0606, CU0610, CU0625, CU0681, CU0707, CU0737, CU0747, CU0752, CU0761, CU0764, CU0765, CU0767, CU0780, CU0790, CU0799, CU0800, CU0803, CU0811
  • the present disclosure provides a compound having a structure of Formula (IId1):
  • R 1 may be a C 1 - C 7 alkyl group or a C 1 -C 7 alkoxy group, wherein R 1 is optionally substituted with one or more substituents selected from the group consisting of an alkyl, an alkoxyl, a halogen, a phenyl group, a cyclic group, a bicyclic group, an alkenyl group, and an alkynyl group, wherein each of the one or more substituents is optionally further substituted with at least one halogen, alkyl group, or alkoxyl group;
  • R2 may be a branched or linear C 1 -C 4 alkoxy group or a C 3 -C 5 cycloalkyl group;
  • R6 may be hydrogen, OH, a C 1 -C 3 alkyl group, or a C 1 -C 3 alkoxyl group;
  • R 13 may be a bond, a C 1 -
  • each R 15 may be hydrogen or a C 1 -C 4 alkyl group
  • R 16 may be a morpholine, a piperazine, or an oxazepane; wherein each R16 is optionally substituted with one or more substituents selected from the group consisting of a C 1 -C 4 alkyl group, a C 3 -C 5 cycloalkyl group, a C 1 - C 3 hydroxyalkyl group, a C 1 -C 4 alkoxy group, a C 1 -C 4 alkylmethoxy group, a C 1 - C 4 alkylethoxy group, -(C 1 -C 3 alkyl)-N(R 15 ) 2 , a C 1 -C 3 alkylpyrrolidine group, an acetyl group, and an oxo group
  • R17 may be hydrogen or a C 1 -C 4 alkyl group
  • R23 may be hydrogen, an alkyl, or a halogen.
  • the compound may be selected from the group consisting of CU0032, CU0033, CU0034, CU0035, CU0036, CU0037, CU0038, CU0039, CU0040, CU0041, CU0042, CU0043, CU0044, CU0045, CU0046, CU0047, CU0048, CU0049, CU0050, CU0051, CU0052, CU0053, CU0054, CU0055, CU0056, CU0057, CU0058, CU0059, CU0060, CU0061, CU0062, CU0248, CU0249, CU0250, CU0251, CU0252, CU0253, CU0254, CU0255, CU0256, CU0257, CU0258, CU0259, CU0260, CU0261 and CU0262.
  • the present disclosure provides a compound having a structure selected from the group consisting of SM0001, SM0002, SM0003, SM0004, SM0005, SM0006, SM0007, SM0008, SM0009, SM0010, SM0011, SM0012, SM0013, SM0014, SM0015, SM0016, SM0017, SM0018, SM0019, SM0020, SM0021, SM0022, SM0023, SM0024, SM0025, SM0026, SM0027, SM0028, SM0029, SM0030, SM0031, SM0032, SM0033, SM0034, SM0035, SM0036, SM0037, SM0038, SM0039, SM0040, SM0041, SM0042, SM0043, SM0044, SM0045, SM0046, SM0047, SM00
  • the present disclosure provides a pharmaceutical composition that includes any of the compounds described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may be formulated for oral delivery.
  • the pharmaceutical composition may have a format selected from the group consisting of a liquid, a tablet, a pill, and a capsule.
  • the present disclosure provides a method of inhibiting complement activity in a biological system by contacting the biological system with a C5 inhibitor, wherein the C5 inhibitor includes any of the compounds described here or a pharmaceutically acceptable salt thereof.
  • the C5 inhibitor may have an equilibrium dissociation constant (KD) for association with C5 of from about 0.01 nM to about 10,000 nM.
  • the C5 inhibitor may inhibit red blood cell lysis with a half maximal inhibitory concentration (IC50) of from about 0.01 nM to about 5,000 nM.
  • the biological system may include one or more of a cell, a tissue, an organ, and a bodily fluid.
  • the biological system may include a subject, wherein the subject is a mammal. The subject may be a human.
  • the present disclosure provides a method of inhibiting complement activity in a subject by administering a compound or pharmaceutical composition disclosed herein to the subject.
  • the complement activity may include C5 activity.
  • the present disclosure provides a method of treating a complement-related indication in a subject by administering a compound or pharmaceutical composition disclosed herein to the subject.
  • the complement-related indication may be selected from the group consisting of paroxysmal nocturnal hemoglobinuria, an
  • the administration may include intravenous, subcutaneous, oral, or topical administration.
  • the subject may be resistant to treatment with eculizumab.
  • the subject may have previously been treated with eculizumab.
  • the present disclosure provides a C5-interacting compound, wherein the C5-interacting compound binds to C5 and includes a compound disclosed herein.
  • the C5-interacting compound may bind to at least one cysteine residue of C5.
  • the C5- interacting compound may inhibit C5 cleavage.
  • the C5-interacting compound may exhibit a kinetic solubility value of from about 10 mM to about 500 mM, wherein the kinetic solubility value is determined for solubility in 0.5 M phosphate buffered saline, pH 7.4.
  • the kinetic solubility value may be from about 20 mM to about 50 mM.
  • the C5-interacting compound may exhibit an apparent permeability (Papp) value for movement across a cell monolayer of from about 0.1 x 10 -6 cm/s to about 30 x 10 -6 cm/s, wherein the P app value is determined by measuring apical to basolateral movement across a Madin Darby canine kidney (MDCK) cell monolayer.
  • Papp apparent permeability
  • the C5-interacting compound may exhibit an efflux ratio of from about 5 to about 150, wherein the efflux ratio is determined by obtaining a P app value for apical to basolateral movement (P app A-B) across the MDCK cell monolayer; obtaining a P app value for basolateral to apical movement (Papp B-A) across the MDCK cell monolayer; and calculating the ratio of P app A-B to P app B-A.
  • Fig.1A is a graph showing flow cytometry counts associated with fluorescently labeled CD59 in an untreated control sample including CD59-deficient cells from PNH patients and donor matched serum.
  • Fig.1B is a graph showing flow cytometry counts associated with fluorescently labeled CD59 in a control sample including CD59-deficient cells from PNH patients and donor matched serum acidified with HCl to induce hemolysis.
  • Fig.1C is a graph showing flow cytometry counts associated with fluorescently labeled CD59 in a sample including CD59-deficient cells from PNH patients, donor matched serum acidified with HCl to induce hemolysis, and eculizumab inhibitor.
  • Fig.1D is a graph showing flow cytometry counts associated with fluorescently labeled CD59 in a sample including CD59-deficient cells from PNH patients, donor matched serum acidified with HCl to induce hemolysis, and SM0001 inhibitor.
  • Fig.2 is a picture of wells from an assay plate, wherein the wells include CD59- deficient cells from PNH patients, donor matched serum acidified with HCl to induce hemolysis, and increasing concentrations of SM0001 inhibitor. In the assay, darker well coloring is indicative of increased hemolysis.
  • Complement-interacting compounds may bind complement components and/or modulate complement activity.
  • complement activity includes the activation of the complement cascade, the formation of cleavage products from a complement component (e.g., C3 or C5), the assembly of downstream complexes following a cleavage event, or any process or event attendant to, or resulting from, the cleavage of a complement component, e.g., C3 or C5.
  • Complement- interacting compounds may include chemical compounds, for example, small molecules or pharmaceutically acceptable salt forms of the small molecules that are capable of interacting with complement components. Some compounds may inhibit complement activation.
  • complement component C5 or“C5” is a protein complex which is cleaved by C5 convertase into at least the cleavage products, C5a and C5b.
  • complement-interacting compounds of the present disclosure may associate with C5, cleavage products of C5, and/or modulate C5 activity. These compounds are referred to herein as“C5-interacting compounds.”
  • C5-interacting compounds that inhibit complement activation at the level of complement component C5 are referred to herein as “C5 inhibitor compounds” or“C5 inhibitors.”
  • Some C5 inhibitors function by preventing the cleavage of C5 to the cleavage products C5a and C5b.
  • C5 inhibitors may inhibit C5 cleavage in a system.
  • a“system” refers to a group of related parts that function together.
  • Such systems include those comprising C5, referred to here as“C5 systems.”
  • C5 systems may include, but are not limited to solutions, matrices, cells, tissues, organs, and bodily fluids (including, but not limited to blood).
  • C5 systems may be biological systems.
  • biological system refers to a cell, a group of cells, a tissue, an organ, a group of organs, an organelle, a biological signaling pathway (e.g., a receptor-activated signaling pathway, a charge-activated signaling pathway, a metabolic pathway, a cellular signaling pathway, etc.), a group of proteins, a group of nucleic acids, or a group of molecules
  • a biological signaling pathway e.g., a receptor-activated signaling pathway, a charge-activated signaling pathway, a metabolic pathway, a cellular signaling pathway, etc.
  • biological systems are“cellular systems.”
  • “cellular system” refers to a biological system that includes one or more cells or one or more components or products of a cell.
  • C5 systems may include in vivo systems, in vitro systems, and/or ex vivo systems. In vivo C5 systems may include or be included in a subject.
  • C5 inhibitor compounds may include suitable reacting groups for reacting with functional groups on a protein.
  • the reacting group may possess C5 inhibiting and/or interacting properties.
  • C5 and other system components may be in solution or may be fixed, e.g., to a solid support, such as in an assay well.
  • C5 systems may further include other components of complement, in some cases including all of the components necessary to form the membrane attack complex (MAC).
  • MAC membrane attack complex
  • C5 inhibitors of the present disclosure may be used to inhibit C5 cleavage in a human subject. Such compounds may find utility in treating various complement-related indications, as described herein.
  • Cleavage of C5 yields the proteolytic products C5a and C5b.
  • the cleavage site of C5 that is cleaved to yield these products is referred to herein as the C5a-C5b cleavage site.
  • site may be used to refer to any position within a polypeptide. Sites include locations on a polypeptide that may be modified, manipulated, altered, derivatized, or varied in response to one or more factors or stimuli.
  • C5b contributes to the formation of the membrane attack complex (MAC) while C5a stimulates the immune system and the inflammatory response.
  • compounds of the present disclosure prevent the cleavage of C5 and therefore may be useful in the treatment of inflammation through the inhibition of inflammatory events including, but not limited to chemotaxis and activation of inflammatory cells (e.g. macrophages, mast cells, neutrophils and platelets), proliferation of endothelial cells and edema.
  • C3, C4, and C5 are functionally inert in their native state until targeted for cleavage into multiple active components. Cleavage of C3 or C4 causes a conformational change that exposes an internal thioester domain.
  • domain when referring to proteins, refers to a motif of a polypeptide having one or more identifiable structural (such as secondary or tertiary structures) or functional characteristics or properties (e.g., binding capacity, serving as a site for protein-protein interactions).
  • an internal thioester linkage between cysteine and glutamine residue side chains is a chemically labile bond that confers the ability of C3 and C4 to bind cell surface and/or biological molecules.
  • the cleavage of C3 and C4 also provides the components of the C5 convertase, either C3bC4bC2a or (C3b)2Bb. (Law, S.K., et al. (1997). Protein Science.6:263-274; van den Elsen, J.M.H., (2002). J. Mol. Biol.322:1103-1115; the contents of each of which are herein incorporated by reference in their entireties).
  • the multiple domain structure of C5 is similar to C3 and C4.
  • the C5 convertase cleaves C5 into the components C5a and C5b.
  • the cleavage of C5 causes a conformational change that exposes the C5b thioester-like domain, which plays a role in C5 binding C6, followed by interactions with C7 and C8 to form the cytolytic MAC.
  • the domain structures of C5 comprise regulatory features that are critical for the processing and downstream activity of complement. (Fredslund, F. et al. (2008). Nature.9:753-760; Hadders, M.A. et al. (2012). Cell Reports.1:200-207).
  • Thrombin acts in the coagulation cascade, a second circulation-based process by which organisms, in response to injury, are able to limit bleeding, restore vascular integrity, and promote healing. Subsequent to vessel damage, tissue factor (TF) is exposed to the circulation, setting off a cascade of proteolytic reactions that leads to the generation of the central coagulation enzyme thrombin, which converts fibrinogen into a fibrin clot.
  • tissue factor thrombin
  • the complement system is activated via three main pathways, all converging with proteolytic activation of the central complement component C3.
  • C5 convertases results in cleavage of C5 at arginine 751 (R751) to liberate a chemotactic and anaphylatoxic C5a fragment and generate C5b.
  • C5b is the initiating factor for assembly of the C5b dependent lytic membrane attack complex (MAC; also known as C5b-9), responsible for destroying damaged cells and pathogens.
  • MAC C5b dependent lytic membrane attack complex
  • compounds of the present disclosure may inhibit thrombin- induced complement activation. Such compounds may therefore be used to treat hemolysis resulting from thrombin-induced complement activation.
  • complement may be activated by additional components of the coagulation and/or inflammation cascades.
  • additional components of the coagulation and/or inflammation cascades For example, other serine proteases with slightly different substrate specificity may act in a similar way. Huber-Lang et al. (2006) showed that thrombin not only cleaved C5 but also in vitro-generated C3a when incubated with native C3 (Huber-Lang, et al., 2006. Nature Med.12(6):682-687; the contents of which are herein incorporated by reference in their entirety).
  • other components of the coagulation pathway such as FXa, FXIa and plasmin, have been found to cleave both C5 and C3.
  • compounds of the present disclosure may inhibit activation of C5 by plasmin, FXa, FIXa, FXIa and other proteases of the coagulation pathway.
  • C5 inhibitors inhibit cleavage of C5 to C5a and C5b fragments. Analysis and detection of such inhibitory activity may be carried out by immunological assays (e.g., ELISAs).
  • immunological assays for detecting C5 inhibitor activity may include ELISAs detecting C5 fragments (e.g. C5a fragments).
  • immunological assays may detect indicators of MAC assembly.
  • HLE Human leukocyte elastase
  • compounds of the present disclosure may inhibit activation of C5 by HLE and other proteases of the inflammation cascade.
  • C5-interacting compounds of the present disclosure may be small molecules.
  • Such small molecule compounds may have a size of from about 100 to about 20000 g/mol (e.g. from about 100 to about 200, to about 300, to about 400, to about 500, to about 600, to about 700, to about 800, to about 900, to about 1000, to about 1100, to about 1200, to about 1300, to about 1400, to about 1500, to about 1600, to about 1700, to about 1800, to about 1900, to about 2000, to about 5000, to about 10000, to about 15000, or to about 20000 g/mol).
  • compounds may have a size of from about 200 to about 1000 g/mol.
  • C5-interacting compounds of the present disclosure may have a topological polar surface area (TPSA) of from about 20 ⁇ 2 to about 250 ⁇ 2 (e.g. from about 20 ⁇ 2 to about 40 ⁇ 2 , to about 60 ⁇ 2 , to about 80 ⁇ 2 , to about 100 ⁇ 2 , to about 120 ⁇ 2 , to about 140 ⁇ 2 , to about 160 ⁇ 2 , to about 180 ⁇ 2 , or to about 200 ⁇ 2 ).
  • TPSA topological polar surface area
  • C5-interacting compounds may have TPSA of from about 40 ⁇ 2 to about 60 ⁇ 2 , to about 80 ⁇ 2 , to about 100 ⁇ 2 , to about 120 ⁇ 2 , to about 140 ⁇ 2 , to about 160 ⁇ 2 , or to about 180 ⁇ 2 .
  • the compounds may have a TPSA of from about 40 ⁇ 2 to about 180 ⁇ 2 .
  • TPSA refers to a predicted sum of surfaces of polar atoms in a molecule.
  • C5-interacting compounds may bind C5.
  • C5 binding may be characterized, for example, by the equilibrium dissociation constant (K D ) for interactions between compounds and C5.
  • K D values may be obtained by surface plasmon resonance (SPR) analysis.
  • C5-interacting compounds of the present disclosure may exhibit a KD for interactions with C5 of from about 0.01 nM to about 10 nM, from about 0.1 nM to about 20 nM, from about 0.5 nM to about 50 nM, from about 1 nM to about 100 nM, from about 50 nM to about 500 nM, from about 200 nM to about 2000 nM, from about 500 nM to about 5000 nM or from about 1000 nM to about 10000 nM.
  • C5 binding may be evaluated using fluorescence polarization. According to such methods, displacement of a fluorescent C5-binding probe may be assessed.
  • small molecule C5-interacting compounds may have properties that offer benefits over biomolecule inhibitors. These may include, but are not limited to, increased membrane permeability and solubility. Membrane permeable small molecules may diffuse in a short period of time inside the cell and therefore provide faster therapeutic effect. Small molecules are, in general, more cost effective due to lower production cost and easier storage/shipping (small molecules do not have similar
  • Small molecules may be designed to be metabolically stable, have favorable bioavailability, and may be suitable for oral delivery. Additionally, small molecules may be designed to be more suitable for different delivery paths, e.g. topical, ocular, intravenous, or subcutaneous.
  • C5-interacting compounds of the present disclosure include C5 inhibitors.
  • urea-derivative complement inhibitors have been described previously (e.g., Zhang et al. in ACS Med. Chem. Lett., 2012, 3(4): 317–21 and International Publication No. WO2013091285, the contents of each of which are herein incorporated by reference in their entirety). These include 1-phenyl-3-(1-phenylethyl) urea derivatives capable of inhibiting C9 deposition through the classical, lectin, and alternative pathways. Such compounds demonstrate selectivity for C9, with no influence on activity of C3 and C4 depositions.
  • C5 inhibitor compounds of the disclosure may include any of the compounds presented in International Publication No. WO2013091285, the contents of which are herein incorporated by reference in their entirety. Such compounds include SM0009 of Table 1.
  • Hemolysis assays may include different formats, but generally involve analyzing the effect of one or more factors on red blood cell lysis.
  • red blood cells may be used that have been sensitized to ensure susceptibility to C5 activity.
  • Such cells may include antibody-sensitized sheep erythrocytes.
  • Sensitized red blood cells may be combined with C5 protein and other complement components in the presence or absence of C5 inhibitors and the level of red blood cell hemolysis may be measured (e.g., through spectrophotometric analysis).
  • Results may be used to characterize inhibitors by half maximal inhibitory concentration (IC50), where the IC50 represents the concentration of inhibitor needed to reduce hemolysis by half.
  • IC50 half maximal inhibitory concentration
  • C5 inhibitor compounds of the present disclosure may inhibit red blood cell lysis with an IC50 of from about 0.01 nM to about 1 nM, from about 0.1 nM to about 10 nM, from about 0.5 nM to about 50 nM, from about 1 nM to about 100 nM, from about 5 nM to about 500 nM, from about 50 nM to about 1000 nM, from about 200 nM to about 2000 nM, from about 400 nM to about 4000 nM, from about 800 nM to about 8000 nM, from about 2500 nM to about 10000 nM, or from about 5000 nM to about 20000 nM.
  • an IC50 of from about 0.01 nM to about 1 nM, from about 0.1 nM to about 10 nM, from about 0.5 nM to about 50 nM, from about 1 nM to about 100 nM, from about 5 nM to about 500 nM, from about 50 n
  • inhibition by C5-interacting compounds may be evaluated by analyzing one or more products of C5 activity. Analysis of C5 activity products may be carried out using standard immunological assays known in the art. Such products may include C5 cleavage products (e.g., C5a or C5b). In some cases, membrane attack complex (MAC) formation is assessed.
  • C5 cleavage products e.g., C5a or C5b.
  • MAC membrane attack complex
  • C5 inhibitors may be evaluated for inhibition of C5 activity arising from specific pathways of activation. Such pathways may include classical, alternative, and lectin pathways. Inhibition of specific pathways may be analyzed according to standard procedures known in the art.
  • C5 inhibitor compounds of the present disclosure may be optimized to improve solubility. In some cases, C5 inhibitor compounds with enhanced solubility may demonstrate improved inhibition of C5 activity.
  • C5 inhibitor compounds of the present disclosure may be optimized to modulate bioavailability.
  • bioavailability refers to the fraction of an administered compound that reaches the systemic circulation.
  • bioavailability of an intravenously administered compound is near 100%, whereas the percentage may be lower, for example, with orally or topically administered compounds due to incomplete absorption.
  • Bioavailability may be determined, for example, by conducting Drug Metabolism and Pharmacokinetics (DMPK) studies. Such studies may be carried out in vivo.
  • DMPK Drug Metabolism and Pharmacokinetics
  • the bioavailability of C5 inhibitor compounds ranges from about 10% to about 100 %, e.g. about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 100%. In some embodiments, the bioavailability is about 30%.
  • C5 inhibitor compounds of the present disclosure may have a KD for C5 of from about 0.01 nM to about 10 nM, from about 0.1 nM to about 20 nM, from about 0.5 nM to about 50 nM, from about 1 nM to about 100 nM, from about 50 nM to about 500 nM, from about 200 nM to about 2000 nM, from about 500 nM to about 5000 nM or from about 1000 nM to about 10000 nM.
  • C5 inhibitor compounds of the present disclosure may bind to C5 with a half-maximal effective concentration (EC 50 ) of from about 0.01 nM to about 10 nM, from about 0.1 nM to about 20 nM, from about 10 nM to about 50 nM, from about 20 nM to about 40 nM, from about 30 nM to about 60 nM, from about 50 nM to about 80 nM, from about 75 nM to about 100 nM, from about 90 nM to about 120 nM, from about 110 nM to about 140 nM, from about 130 nM to about 160 nM, from about 150 nM to about 180 nM, from about 170 nM to about 200 nM, from about 190 nM to about 220 nM, from about 210 nM to about 240 nM, from about 230 nM to about 260 nM, from about 250 nM to about 280 n
  • EC 50 half-max
  • C5 inhibitor compounds of the present disclosure may inhibit red blood cell lysis with an IC50 of from about 0.01 nM to about 10 nM, from about 0.1 nM to about 20 nM, from about 10 nM to about 50 nM, from about 20 nM to about 40 nM, from about 30 nM to about 60 nM, from about 50 nM to about 80 nM, from about 75 nM to about 100 nM, from about 90 nM to about 120 nM, from about 110 nM to about 140 nM, from about 130 nM to about 160 nM, from about 150 nM to about 180 nM, from about 170 nM to about 200 nM, from about 190 nM to about 220 nM, from about 210 nM to about 240 nM, from about 230 nM to about 260 nM, from about 250 nM to about 280 nM, from about 270 nM
  • C5 inhibitor compounds of the present disclosure may inhibit the production of C5a with an IC 50 of from about 0.01 nM to about 10 nM, from about 0.1 nM to about 20 nM, from about 10 nM to about 50 nM, from about 20 nM to about 40 nM, from about 30 nM to about 60 nM, from about 50 nM to about 80 nM, from about 75 nM to about 100 nM, from about 90 nM to about 120 nM, from about 110 nM to about 140 nM, from about 130 nM to about 160 nM, from about 150 nM to about 180 nM, from about 170 nM to about 200 nM, from about 190 nM to about 220 nM, from about 210 nM to about 240 nM, from about 230 nM to about 260 nM, from about 250 nM to about 280 nM, from about 270 n
  • an IC 50 of from
  • C5 inhibitor compounds of the present disclosure may inhibit the mannose-binding lectin (MBL) complement pathway with an IC50 of from about 0.01 nM to about 10 nM, from about 0.1 nM to about 20 nM, from about 10 nM to about 50 nM, from about 20 nM to about 40 nM, from about 30 nM to about 60 nM, from about 50 nM to about 80 nM, from about 75 nM to about 100 nM, from about 90 nM to about 120 nM, from about 110 nM to about 140 nM, from about 130 nM to about 160 nM, from about 150 nM to about 180 nM, from about 170 nM to about 200 nM, from about 190 nM to about 220 nM, from about 210 nM to about 240 nM, from about 230 nM to about 260 nM, from about 250 nM to about 280
  • MBL mannose-binding
  • the C5 inhibitor compounds may inhibit the alternative complement pathway with an IC 50 of from about 0.01 nM to about 10 nM, from about 0.1 nM to about 20 nM, from about 10 nM to about 50 nM, from about 20 nM to about 40 nM, from about 30 nM to about 60 nM, from about 50 nM to about 80 nM, from about 75 nM to about 100 nM, from about 90 nM to about 120 nM, from about 110 nM to about 140 nM, from about 130 nM to about 160 nM, from about 150 nM to about 180 nM, from about 170 nM to about 200 nM, from about 190 nM to about 220 nM, from about 210 nM to about 240 nM, from about 230 nM to about 260 nM, from about 250 nM to about 280 nM, from about 270 nM to about 300
  • an IC 50 of from about
  • the structures of the C5-interacting compounds (such as C5 inhibitors) of the present disclosure may be encompassed by the generic structure of Formula
  • Z A is N or CR2
  • Z B is N or CR1
  • Z C is N or CR5, with a proviso that
  • R1, R2, or R5 is independently H, alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted;
  • R3 or R4 is independently alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted;
  • R6 or R7 is independently H or an alkyl group, wherein the alkyl group is optional substituted; optionally, R6 and R7, together with the nitrogens to which they are attached and the carbonyl group, may form a 5 to 7-membered heterocycle which may be optionally substituted;
  • R8 is an alkyl group, wherein the alkyl group is optional substituted; optionally, R8 and R7, together with the nitrogen to which they are attached, may for a 5 to 6-membered heterocycle which may be optionally substituted.
  • R1, R2 and R5 are H.
  • R3 is -OCH3.
  • R4 is an alkoxyl group such as or
  • R8 is a substituted alkyl group with a structure of , wherein R9 or R10 independently is H, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, aryl, heteroaryl, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl group, or hetero multicyclic alkyl group, wherein the alkyl, alkenyl, alkynyl, alkoxy, ether, amine, aryl, heteroaryl group, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl, or hetero multicyclic alkyl group is optional substituted.
  • R9 is an alkyl group.
  • R9 is H.
  • R10 is an optionally substituted cyclic group.
  • the cyclic group may be saturated, aromatic, non-aromatic, unsaturated, or partially unsaturated.
  • the cyclic group may be aryl, heteroaryl, multicyclic, or multi-heterocyclic.
  • the heteroatom of the heteroaryl or multi-heterocyclic group may be O, N, or S.
  • R8 is not .
  • the structures of the C5-interacting compounds (such as C5 inhibitors) of the present disclosure may be encompassed by the generic structure of Formula (200):
  • R1, R2, or R5 is independently H, alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted;
  • R3 or R4 is independently alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted;
  • R6 or R7 is independently H or an alkyl group, wherein the alkyl group is optional substituted; optionally, R6 and R7, together with the nitrogens to which they are attached and the carbonyl group, may form a 5 to 7-membered heterocycle which may be optionally substituted;
  • R8 is an alkyl group, wherein the alkyl group is optional substituted; optionally, R8 and R7, together with the nitrogen to which they are attached, may for a 5 to 6-membered heterocycle which may be optionally substituted.
  • R1, R2 and R5 are H.
  • R3 is -OCH3.
  • R4 is an alkoxyl group such as or .
  • R8 is a substituted alkyl group with a structure of , wherein R9 or R10 independently is H, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, aryl, heteroaryl, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl group, or hetero multicyclic alkyl group, wherein the alkyl, alkenyl, alkynyl, alkoxy, ether, amine, aryl, heteroaryl group, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl, or hetero multicyclic alkyl group is optional substituted.
  • R9 is an alkyl group.
  • R9 is H.
  • R10 is an optionally substituted cyclic group.
  • the cyclic group may be saturated, aromatic, non-aromatic, unsaturated, or partially unsaturated.
  • the cyclic group may be aryl, heteroaryl, multicyclic, or multi-heterocyclic.
  • the heteroatom of the heteroaryl or multi-heterocyclic group may be O, N, or S.
  • R8 is not .
  • the structures of the C5-interacting compounds (such as C5 inhibitors) of the present disclosure may be encompassed by the generic structure of Formula
  • R2 or R5 is independently H, alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted;
  • R3 or R4 is independently alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted;
  • R6 or R7 is independently H or an alkyl group, wherein the alkyl group is optional substituted; optionally, R6 and R7, together with the nitrogens to which they are attached and the carbonyl group, may form a 5 to 7-membered heterocycle which may be optionally substituted;
  • R8 is an alkyl group, wherein the alkyl group is optional substituted; optionally, R8 and R7, together with the nitrogen to which they are attached, may for a 5 to 6-membered heterocycle which may be optionally substituted.
  • R2 and R5 are H.
  • R3 is -OCH3.
  • R4 is an alkoxyl group such as or .
  • R8 is a substituted alkyl group with a structure of , wherein R9 or R10 independently is H, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, aryl, heteroaryl, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl group, or hetero multicyclic alkyl group, wherein the alkyl, alkenyl, alkynyl, alkoxy, ether, amine, aryl, heteroaryl group, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl, or hetero multicyclic alkyl group is optional substituted.
  • R9 is an alkyl group.
  • R9 is H.
  • R10 is an optionally substituted cyclic group.
  • the cyclic group may be saturated, aromatic, non-aromatic, unsaturated, or partially unsaturated.
  • the cyclic group may be aryl, heteroaryl, multicyclic, or multi-heterocyclic.
  • the heteroatom of the heteroaryl or multi-heterocyclic group may be O, N, or S.
  • R8 is not .
  • the structures of the C5-interacting compounds (such as C5 inhibitors) of the present disclosure may be encompassed by the generic structure of Formula
  • R1 or R2 is independently H, alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted;
  • R3 or R4 is independently alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted;
  • R6 or R7 is independently H or an alkyl group, wherein the alkyl group is optional substituted; optionally, R6 and R7, together with the nitrogens to which they are attached and the carbonyl group, may form a 5 to 7-membered heterocycle which may be optionally substituted;
  • R8 is an alkyl group, wherein the alkyl group is optional substituted; optionally, R8 and R7, together with the nitrogen to which they are attached, may for a 5 to 6-membered heterocycle which may be optionally substituted.
  • R1 and R2 are H.
  • R3 is -OCH3.
  • R4 is an alkoxyl group such as or .
  • R8 is a substituted alkyl group with a structure of , wherein R9 or R10 independently is H, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, aryl, heteroaryl, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl group, or hetero multicyclic alkyl group, wherein the alkyl, alkenyl, alkynyl, alkoxy, ether, amine, aryl, heteroaryl group, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl, or hetero multicyclic alkyl group is optional substituted.
  • R9 is an alkyl group.
  • R9 is H.
  • R10 is an optionally substituted cyclic group.
  • the cyclic group may be saturated, aromatic, non-aromatic, unsaturated, or partially unsaturated.
  • the cyclic group may be aryl, heteroaryl, multicyclic, or multi-heterocyclic.
  • the heteroatom of the heteroaryl or multi-heterocyclic group may be O, N, or S.
  • R8 is not .
  • the structures of the C5-interacting compounds (such as C5 inhibitors) of the present disclosure may be encompassed by the generic structure of Formula
  • R2 is H, alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted;
  • R3 or R4 is independently alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted;
  • R6 or R7 is independently H or an alkyl group, wherein the alkyl group is optional substituted, and wherein R6 and R7, together with the nitrogens to which they are attached and the carbonyl group, may form a 5 to 7-membered heterocycle which may be optionally substituted;
  • R8 is an alkyl group, wherein the alkyl group is optional substituted; optionally, R8 and R7, together with the nitrogen to which they are attached, may for a 5 to 6-membered heterocycle which may be optionally substituted.
  • R2 is H.
  • R3 is -OCH3.
  • R4 is an alkoxyl group such as or
  • R8 is a substituted alkyl group with a structure of , wherein R9 or R10 independently is H, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, aryl, heteroaryl, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl group, or hetero multicyclic alkyl group, wherein the alkyl, alkenyl, alkynyl, alkoxy, ether, amine, aryl, heteroaryl group, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl, or hetero multicyclic alkyl group is optional substituted.
  • R9 is an alkyl group.
  • R9 is H.
  • R10 is an optionally substituted cyclic group.
  • the cyclic group may be saturated, aromatic, non-aromatic, unsaturated, or partially unsaturated.
  • the cyclic group may be aryl, heteroaryl, multicyclic, or multi-heterocyclic.
  • the heteroatom of the heteroaryl or multi-heterocyclic group may be O, N, or S.
  • R8 is not
  • the structures of the C5-interacting compounds (such as C5 inhibitors) of the present disclosure may be encompassed by the generic structure of Formula
  • R1 or R5 is independently H, alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted;
  • R3 or R4 is independently alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted;
  • R6 or R7 is independently H or an alkyl group, wherein the alkyl group is optional substituted, and wherein R6 and R7, together with the nitrogens to which they are attached and the carbonyl group, may form a 5 to 7-membered heterocycle which may be optionally substituted;
  • R8 is an alkyl group, wherein the alkyl group is optional substituted; optionally, R8 and R7, together with the nitrogen to which they are attached, may for a 5 to 6-membered heterocycle which may be optionally substituted.
  • R2 is H.
  • R3 is -OCH3.
  • R4 is an alkoxyl group such as or .
  • R8 is a substituted alkyl group with a structure of , wherein R9 or R10 independently is H, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, aryl, heteroaryl, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl group, or hetero multicyclic alkyl group, wherein the alkyl, alkenyl, alkynyl, alkoxy, ether, amine, aryl, heteroaryl group, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl, or hetero multicyclic alkyl group is optional substituted.
  • R9 is an alkyl group.
  • R9 is H.
  • R10 is an optionally substituted cyclic group.
  • the cyclic group may be saturated, aromatic, non-aromatic, unsaturated, or partially unsaturated.
  • the cyclic group may be aryl, heteroaryl, multicyclic, or multi-heterocyclic.
  • the heteroatom of the heteroaryl or multi-heterocyclic group may be O, N, or S.
  • R8 is not
  • the structures of the C5-interacting compounds (such as C5 inhibitors) of the present disclosure may be encompassed by the generic structure of Formula
  • R3 or R4 is independently alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted;
  • R11 is H or an alkyl group, wherein the alkyl group is optional substituted
  • R12 is H, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, heteroaryl, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl group, or hetero multicyclic alkyl group, wherein the alkyl, alkenyl, alkynyl, alkoxy, ether, amine, aryl, heteroaryl group, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl, or hetero multicyclic alkyl group is optional substituted;
  • R13 is H, halogen, -CN, -CF3, or a C 1 -C 3 alkyl group
  • Z D is selected from N or CR 14 , wherein R14 is H or an alkyl group, wherein the alkyl group is optionally substituted;
  • Z E is selected from N or CH.
  • R3 and R4 are independently C3-C8 alkyl, C3-C8 cyclic alkyl, C3-C8 alkenyl, C3-C8 alkynyl, halogen, hydroxyl, C3-C8 alkoxyl, aryl, or heteroaryl group.
  • R3 is -OCH3.
  • R4 is an alkoxyl group such as or
  • R12 comprises an amide group.
  • C5 inhibitor compounds having a structure according to Formula (700) include CU0019-CU0032, CU0035, CU0036, CU0039, CU0041, CU0043, CU0044, CU0046, CU0048-CU0051, CU0053, CU0054, CU0056, CU0057, CU0059- CU0062, CU00228, CU0229, CU0231, CU0232, CU0234, CU0235, CU0239-CU0262, CU00500, CU0502, CU0504, CU0506, CU0508-CU0510, CU0513-CU0516, CU0518- CU0530, CU0532-CU0535, CU0538-CU0541, CU0543, CU-0547, CU0549, CU0551, CU0553,
  • the structures of the C5-interacting compounds (such as C5 inhibitors) of the present disclosure may be encompassed by the generic structure of Formula (701):
  • R11 is H or a methyl group
  • R13 is H, halogen, -CN, -CF3, or a C 1 -C 3 alkyl group
  • R15 or R16 independently, is H, alkyl, aryl, heteroaryl, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl group, or hetero multicyclic alkyl group, wherein the alkyl, aryl, heteroaryl group, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl, or hetero multicyclic alkyl group is optional substituted; optionally, R15 and R16, together with the nitrogen they are attached, form a 3 to 8 membered heterocyclic group, wherein the heterocyclic group may be optionally substituted;
  • R17 is halogen, an alkyl group, or an alkoxyl group
  • R18 is an alkyl group
  • Z D is selected from N or CR14, wherein R14 is H or an alkyl group, wherein the alkyl group is optionally substituted.
  • R13 is H or Cl.
  • R17 is a C3-C8 alkyl, or C3-C8 alkoxyl group.
  • R18 is a C3-C8 alkyl group.
  • R17 is -OCH3.
  • Z D is selected form N or CH.
  • R15 and R16 are both C 1 -C 3 alkyl groups, such as methyl groups.
  • R15 and R16 together with the nitrogen they are attached to, form a 6-membered non-aromatic heterocyclic group.
  • the nitrogen they are attached to form a 6-membered non-aromatic heterocyclic group.
  • R17 is an alkyl group, wherein the alkyl group is optionally substituted.
  • R17 is an alkyl group substituted with an amine group.
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (701) include CU0025-CU0031, CU0035, CU0036, CU0043, CU0044, CU0046, CU0048-CU0051, CU0053, CU0054, CU0056, CU0057, CU0059-CU0062, CU00228, CU0229, CU0231, CU0232, CU0235, CU0239, CU0242-CU0247, CU0252, CU0253, CU0255-CU0262, CU0502, CU0504, CU0506, CU0508-CU0510, CU0515, CU0516, CU0518-CU0524, CU0526, CU0528-CU0530, CU0532-CU0535, CU0538-CU0541, CU0543, CU0549, CU0553, CU0557, CU0560,
  • C5-interacting compounds of the present disclosure may include any one of SM0001-SM0121, SM0200-SM0219, C5INH-0294, C5INH-0296, C5INH-0298, C5INH-0303, C5INH-0310, C5INH-0311, C5INH-0315, C5INH-0316, C5INH-0317, C5INH-0318, C5INH-0319, C5INH-0321, C5INH-0323, C5INH-0324, C5INH-0326, C5INH-0329, C5INH-0330, C5INH-0333, C5INH-0335, C5INH-0336, C5INH-0338, C5INH-0339, C5INH-0340, C5INH-0342, C5INH-0343, C5INH-0348, C5INH-03
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (Ia):
  • R 1 is any suitable functional group, such as an alkyl, an alkenyl, or an alkynyl, wherein each of the alkyl, alkenyl, or alkynyl is optionally further substituted; and wherein R2 is any suitable functional group, such as a phenyl group, wherein the phenyl group is optionally substituted, such as with one or more halogens.
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (Ia) include SM0200, SM0201, SM0202, and SM0203.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (Ib):
  • R3 is any suitable functional group, such as -OH or -N(R4)2, and
  • each R4 is independently any suitable functional group, such as hydrogen, an alkyl group, a cyclic group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein each group may be further substituted; or the two R4 groups may form a heterocyclic group, which optionally may be further substituted; wherein the cyclic group or the heterocyclic
  • group may comprise .
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (Ib) include SM0204, SM0205, SM0206, SM0207, SM0208, SM0209, SM0210, SM0211, SM0212, SM0213, SM0214, SM0215, and SM0216.
  • C5 inhibitor compounds have a structure according to Formula (Ic):
  • R 5 is an optionally substituted cyclic group.
  • the cyclic group may be saturated, aromatic, non-aromatic, unsaturated, or partially unsaturated.
  • the cyclic group may be aryl, heteroaryl, multicyclic, or multi-heterocyclic.
  • the heteroatom of the heteroaryl or multi-heterocyclic group may be O, N, or S.
  • R 5 is selected from the group consisting of
  • each group may be further substituted.
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (Ic) include C5INH-0294, C5INH-0296, C5INH-0298, C5INH-0303, C5INH-0310, C5INH-0311, C5INH-0317, C5INH-0318, C5INH-0319, C5INH-0321, C5INH-0323, C5INH-0324, C5INH-0326, C5INH-0329, C5INH-0330, C5INH-0333, C5INH-0335, C5INH-0338, C5INH-0339, C5INH-0340, C5INH-0342, C5INH-0343, C5INH-0348, C5INH-0361, C5INH-0369, C5INH-0370, C5INH-0377, C5INH-0381, C5INH-03
  • C5 inhibitor compounds have a structure according to Formula (Id):
  • R 5 is an optionally substituted cyclic group.
  • the cyclic group may be saturated, aromatic, non-aromatic, unsaturated, or partially unsaturated.
  • the cyclic group may be aryl, heteroaryl, multicyclic, or multi-heterocyclic.
  • the heteroatom of the heteroaryl or multi-heterocyclic group may be O, N, or S.
  • R 5 is selected from the group consisting of
  • each group may be further substituted.
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (Id) include C5INH-0315, C5INH-0316, and C5INH-0395.
  • C5 inhibitor compounds have a structure according to Formula (Ie):
  • R 1 is an optionally substituted alkyl group or alkoxyl group.
  • R1 is selected from -OC 4 H 9 , -OC 6 H 13 , - OC7H15, -NH(C6H13),
  • a phenyl group a toluene group, a
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (Ie) include C5INH-0336, C5INH-0349, C5INH-0350, C5INH-0357, C5INH-0367, C5INH-0406, C5INH-0432, C5INH-0477, and C5INH-0469.
  • C5 inhibitor compounds have a structure according to Formula (If):
  • R 5 is selected from hydrogen, a C1-C8 alkyl group, -CO-NH 2, -CO-NH-OH, aryl, and a heteroaryl group, wherein each group may be substituted with groups such as, but not limited to, a C 1 -C 6 aliphatic group, -OH, -O-(C 1 - C 4 alkyl), halogen, -CF 3 , nitrile, -COOH, -CO-NH 2 , -CO-O-NH 2 , -OCF 3 , -N(H) (C 1 -C 4 alkyl), and -N-(C 1 -C 4 alkyl) 2 .
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (If) include C5INH-0486 and C5INH-0512.
  • C5 inhibitor compounds have a structure according to Formula (Ig):
  • R3 is selected from wherein each group may be further substituted
  • L 1 may be absent or selected from the group consisting of -C 1 -C 6 - alkyl-, -C 1 -C 6 - alkenyl-, - cycloalkyl-, -heterocycle-, -aryl-, and -heteroaryl-, wherein any -CH- may be optionally replaced by -O-, -cycloalkyl-NH-, -alkyl-NH-, -N(R 6 )-, -N(R 6 )-CO-N(R 7 )-, -N(R 6 )-CO-, - CH 6
  • C5 inhibitor compounds have a structure according to Formula (Ih):
  • R4 is selected from -CH 2 COOH, -COOMe, -CH 2 -CO-NH 2 , -CH 2 -CO-N(Me) 2 , -CH 2 -NH 2 , -CH 2 -NH-CO-CH 3 , -CH 2 -NH-SO 2 -CH 3 , -CH 2 -NH-CO-C 4 H9, -CH 2 -NH-CO-
  • L 1 may be absent or selected from the group consisting of -C 1 -C 6 - alkyl-, -C 1 -C 6 - alkenyl-, -cycloalkyl-, -heterocycle-, -aryl-, and -heteroaryl-, wherein any -CH- may be optionally replaced by -O-, -cycloalkyl-NH-, -alkyl-NH-, -N(R 6 )-, -N(R 6 )-CO-N(R 7 )-, - N(R 6 )-CO-, -CH 2 -CO-N(R 7 )-, -N(R 6 )-SO 2 -N(R 7 )-, -SO 2 -N(R 7 )-, -N(R 7 )-SO 2 -, -CO-N(R 7 )-, - O-CO-N(R 7 )-, -N(R 7
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (Ih) include C5INH-0355, C5INH-0397, C5INH-0422, C5INH-0440, C5INH-0504, C5INH-0509, C5INH-0510, C5INH-0527, C5INH-0539, and C5INH-0547.
  • compounds of the present disclosure are C5-interacting compounds. Such compounds may include any of those listed in Table 2, including CU0001- CU0262 and CU0500-CU0847.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIa):
  • a 1, 2 or 3;
  • b is 1 or 2;
  • R1 is a C 1 -C7 alkyl group, C 1 -C7 alkoxy group, wherein R1 is optionally substituted with one or more substituents, such as alkyl, alkoxyl, halogen, a phenyl group, a cyclic group, a bicyclic group, an alkenyl group, or an alkynyl group, wherein each of these groups is optionally further substituted, such as with at least one halogen, an alkyl group, or an alkoxyl group;
  • R 2 is a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, or a C 3 -C 5 cycloalkyl group;
  • R 6 is independently hydrogen, OH, a C 1 -C 3 alkyl group, or a C 1 -C 3 alkoxyl group; wherein comprises at least one aryl ring or a heteroaryl ring, optionally substituted with one or more R 5 groups; wherein each R5 is independently a suitable functional group, such as hydrogen, a halogen, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, a C 3 -C 6 cycloalkyl group, a C 3 -C 6 heterocycle group, a pyridine or alkylpyridine optionally substituted with one or more C 1 -C 4 alkyl groups, a pyrrolidinone or alkylpyrrolidinone optionally substituted with one or more C 1 - C 4 alkyl groups, a triazole or alkyltriazole optionally substituted with a C 1 -C 4 alkyl group, - (C 1 -C 3 alkyl
  • each R15 is independently selected from hydrogen or a C 1 -C 4 alkyl group; and wherein R 16 is selected from a group consisting of a pyrrolidine, a morpholine, a piperazine, and an oxazepane; and wherein each R16 is optionally substituted with one or more substituents selected from the group consisting of: C 1 -C 4 alkyl group, a C 3 -C 5 cycloalkyl group, C 1 -C 3 hydroxyalkyl group, C 1 -C 4 alkoxy group, C 1 -C 4 alkylmethoxy group, C 1 - C 4 alkylethoxy group, -(C 1 -C 3 alkyl)-N(R 15 ) 2 , an C 1 -C 3 alkylpyrrolidine group, an acetyl group, and an oxo group.
  • R1 is , ,
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIa) include CU0001, CU0002, CU0003, CU0004, CU0005, CU0006, CU0007, CU0008, CU0009, CU0010, CU0011, CU0012, CU0013, CU0014, CU0015, CU0016, CU0017, CU0018, CU0019, CU0020, CU0021, CU0022, CU0023, CU0024, CU0025, CU0026, CU0027, CU0028, CU0029, CU0030, CU0031, CU0032, CU0033, CU0034, CU0035, CU0036, CU0037, CU0038, CU0039, CU0040, CU0041, CU0042, CU0043, CU0044, CU0045, CU0046, CU0047, CU0048
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIb):
  • a 1, 2 or 3;
  • b is 1 or 2;
  • X1 is carbon or nitrogen
  • R1 is a C 1 -C7 alkyl group, C 1 -C7 alkoxy group, wherein R1 is optionally substituted with one or more substituents, such as alkyl, alkoxyl, halogen, a phenyl group, a cyclic group, a bicyclic group, an alkenyl group, or an alkynyl group, wherein each of these groups is optionally further substituted, such as with at least one halogen, an alkyl group, or an alkoxyl group;
  • R2 is a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group, or a C 3 -C 5 cycloalkyl group;
  • R6 is independently hydrogen, OH, a C 1 -C 3 alkyl group, or a C 1 -C 3 alkoxyl group; wherein R 7 is any suitable functional group, such as hydrogen, a C 1 -C 3 alkyl group, C 1 -C 3 alkoxy, a C 3 -C 5 cycloalkyl group, or a halogen;
  • R8 is any suitable functional group, such as hydrogen, a halogen or a C 1 -C 3 alkyl group
  • R 10 is any suitable functional group, such as hydrogen, a halogen, a C 1 -C 3 alkyl group, or a cyclic group;
  • each R 9 group is optionally further substituted with one or more halogens, -OH, alkyl, or alkoxyl groups;
  • R1 is N-(1-[0159]
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIb) include CU0001, CU0002, CU0003, CU0004, CU0005, CU0006, CU0007, CU0008, CU0009, CU0010, CU0011, CU0012, CU0013, CU0014, CU0015, CU0016, CU0017, CU0018, CU0100, CU0101, CU0102, CU0103, CU0104, CU0105, CU0106, CU0107, CU0108, CU0109, CU0110, CU0111, CU0112, CU0113, CU0114, CU0115, CU0116, CU0117, CU0118, CU0119, CU0120, CU0121, CU0122, CU0123, CU0124, CU0125, CU0126, CU0127, CU0128, CU0129
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIc):
  • a 1, 2 or 3;
  • X 2 is carbon or nitrogen
  • X3 is nitrogen or oxygen, and R13 and R14 are not present when X3 is oxygen;
  • X4 is carbon, nitrogen, or oxygen, and R18 is not present when X4 is oxygen;
  • R 1 is a C 1 -C 7 alkyl group or C 1 -C 7 alkoxy group, wherein R 1 is optionally substituted with one or more substituents selected from the group consisting of an alkyl, an alkoxyl, a halogen, a phenyl group, a cyclic group, a bicyclic group, an alkenyl group, and, an alkynyl group, wherein each of the one or more substituents is optionally further substituted with at least one halogen, an alkyl group, or an alkoxyl group;
  • R2 is a branched or linear C 1 -C 4 alkoxy group, or a C 3 -C 5 cycloalkyl group;
  • R 6 is hydrogen, OH, a C 1 -C 3 alkyl group, or a C 1 -C 3 alkoxyl group;
  • each R15 is independently any suitable functional group, such as hydrogen or a C 1 - C 4 alkyl group.
  • R 16 is any suitable functional group, such as a morpholine, a piperazine, and an oxazepane; wherein each R16 is optionally substituted with one or more substituents selected from the group consisting of: C 1 -C 4 alkyl group, a C 3 -C 5 cycloalkyl group, C 1 - C 3 hydroxyalkyl group, C 1 -C 4 alkoxy group, C 1 -C 4 alkylmethoxy group, C 1 -C 4 alkylethoxy group, -(C 1 -C 3 alkyl)-N(R 15 ) 2 , an C 1 -C 3 alkylpyrrolidine group, an acetyl group, and an oxo group;
  • R 17 is any suitable functional group, such as hydrogen or a C 1 -C 4 alkyl group
  • R 18 is any suitable functional group, such as hydrogen, a halogen, or an alkyl group.
  • X2 when X2 is nitrogen, X3 is nitrogen and X4 is carbon.
  • R 1 is , ,
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIc) include CU0019, CU0020, CU0021, CU0022, CU0023, CU0024, CU0025, CU0026, CU0027, CU0028, CU0029, CU0030, CU0031, CU0032, CU0033, CU0034, CU0035, CU0036, CU0037, CU0038, CU0039, CU0040, CU0041, CU0042, CU0043, CU0044, CU0045, CU0046, CU0047, CU0048, CU0049, CU0050, CU0051, CU0052, CU0053, CU0054, CU0055, CU0056, CU0057, CU0058, CU0059, CU0060, CU0061, CU0062, CU0063, CU0064
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IId):
  • a 1, 2 or 3;
  • R1 is a C 1 -C7 alkyl group, C 1 -C7 alkoxy group, wherein R1 is optionally substituted with one or more substituents, such as alkyl, alkoxyl, halogen, a phenyl group, a cyclic group, a bicyclic group, an alkenyl group, or an alkynyl group, wherein each of these groups is optionally further substituted, such as with at least one halogen, an alkyl group, or an alkoxyl group;
  • R 2 is a branched or linear C 1 -C 4 alkoxy group, or a C 3 -C 5 cycloalkyl group;
  • R 6 is hydrogen, OH, a C 1 -C 3 alkyl group, or a C 1 -C 3 alkoxyl group ;
  • R13 is a bond or a C 1 -C 3 alkyl group
  • each R 15 is independently any suitable functional group such as hydrogen or a C 1 - C 4 alkyl group
  • R 16 is any suitable functional group such as a morpholine, a piperazine, and an oxazepane; wherein each R 16 is optionally substituted with one or more substituents selected from the group consisting of: C 1 -C 4 alkyl group, a C 3 -C 5 cycloalkyl group, C 1 - C3 hydroxyalkyl group, C 1 -C 4 alkoxy group, C 1 -C 4 alkylmethoxy group, C 1 -C 4 alkylethoxy group, -(C 1 -C 3 alkyl)-N(R 15 ) 2 , an C 1 -C 3 alkylpyrrolidine group, an acetyl group, and an oxo group;
  • R17 is any suitable functional group such as hydrogen or a C 1 -C 4 alkyl group
  • R 19 is any suitable functional group such as hydrogen, an alkyl, or a halogen
  • R20 is any suitable functional group hydrogen, an alkyl, or a halogen
  • R21 is any suitable functional group hydrogen, an alkyl, or a halogen
  • R22 is any suitable functional group hydrogen, an alkyl, or a halogen.
  • R1 is , ,
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IV) include CU0019, CU0020, CU0021, CU0022, CU0023, CU0024, CU0025, CU0026, CU0027, CU0028, CU0029, CU0030, CU0031, CU0228, CU0229, CU0230, CU0231, CU0232, CU0233, CU0234, CU0235, CU0236, CU0237, CU0238, CU0239, CU0240, CU0241, CU0242, CU0243, CU0244, CU0245, CU0246, and CU0247.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IId1):
  • a 1, 2 or 3;
  • R1 is a C 1 -C7 alkyl group, C 1 -C7 alkoxy group, wherein R1 is optionally substituted with one or more substituents, such as alkyl, alkoxyl, halogen, a phenyl group, a cyclic group, a bicyclic group, an alkenyl group, or an alkynyl group, wherein each of these groups is optionally further substituted, such as with at least one halogen, an alkyl group, or an alkoxyl group;
  • R2 is a branched or linear C 1 -C 4 alkoxy group, or a C 3 -C 5 cycloalkyl group; wherein R6 is hydrogen, OH, a C 1 -C 3 alkyl group, or a C 1 -C 3 alkoxyl group; wherein R13 is a bond, a C 1 -C 3 alkyl group, a group that comprises a carbonyl group, cyclic group, or heterocyclic group;
  • each R15 is independently any suitable functional group such as hydrogen or a C 1 - C 4 alkyl group; and wherein R 16 is selected from a group consisting of a morpholine, a piperazine, and an oxazepane; wherein each R 16 is optionally substituted with one or more substituents selected from the group consisting of: C 1 -C 4 alkyl group, a C 3 -C 5 cycloalkyl group, C 1 -C 3 hydroxyalkyl group, C 1 -C 4 alkoxy group, C 1 -C 4 alkylmethoxy group, C 1 - C 4 alkylethoxy group, -(C 1 -C 3 alkyl)-N(R 15 ) 2 , an C 1 -C 3 alkylpyrrolidine group, an acetyl group, and an oxo group;
  • R17 is any suitable functional group such as hydrogen or a C 1 -C 4 alkyl group; and wherein R 23 is any suitable functional group such as hydrogen, an alkyl, or a halogen.
  • R 1 is , ,
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IId1) include CU0032, CU0033, CU0034, CU0035, CU0036, CU0037, CU0038, CU0039, CU0040, CU0041, CU0042, CU0043, CU0044, CU0045, CU0046, CU0047, CU0048, CU0049, CU0050, CU0051, CU0052, CU0053, CU0054, CU0055, CU0056, CU0057, CU0058, CU0059, CU0060, CU0061, CU0062, CU0248, CU0249, CU0250, CU0251, CU0252, CU0253, CU0254, CU0255, CU0256, CU0257, CU0258, CU0259, CU0260, CU0261, CU0261, CU
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIe):
  • X1 is CH or N
  • R1 is H, halogen (such as Cl, F, Br or I), -CN, -CF3, or a C 1 -C 3 alkyl group;
  • R2 or R3, independently, is H, alkyl, aryl, heteroaryl, cyclic alkyl, heterocyclic alkyl, a multicyclic alkyl group, or a hetero multicyclic alkyl group, wherein the alkyl, aryl, heteroaryl group, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl, or hetero multicyclic alkyl group is optional substituted; optionally, R2 and R3, together with the nitrogen they are attached, form a 3 to 8 membered heterocyclic group, wherein the heterocyclic group may be optionally substituted; and
  • R4 is H or a C 1 -C 3 alkyl group.
  • R2 and R3 are both C 1 -C 3 alkyl groups.
  • R4 is H.
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIe) include CU0025, CU0028, CU0029, CU0030, CU0031, CU0035, CU0043, CU0046, CU0048, CU0049, CU0050, CU0051, CU0053, CU0056, CU0057, CU0060, CU0062, CU0231, CU0232, CU0235, CU0239, CU0243, CU0244, CU0245, CU0246, CU0247, CU0255, CU0257, CU0258, CU0260, CU0261, CU0504, CU0506, CU0508, CU0509, CU0510, CU0518, CU0519, CU0521, CU0526, CU0528, CU0529, CU0533, CU0534, CU0535, CU0538
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIf):
  • X1 is CH or N
  • R1 is H, halogen (such as Cl, F, Br or I), -CN, -CF3, or a C 1 -C3 alkyl group;
  • R2 or R3, independently, is alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxyl, ether, CN, amine, amide, aryl, or heteroaryl, wherein the alkyl, cyclic alkyl, alkenyl, alkynyl, alkoxyl, ether, amine, aryl, or heteroaryl group is optionally substituted; and wherein R4 is H or a C 1 -C 3 alkyl group.
  • R2 and R3 are both alkoxyl groups.
  • R2 is -OCH3.
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIf) include CU0025, CU0026,CU0027, CU0035, CU0036, CU0231, CU0232, CU0252, CU0253, CU0256, CU0258, CU0259, CU0261, CU0262, CU0508, CU0515, CU0516, CU0532, CU0535, CU0543, CU0582, CU0591, CU0595, CU0602, CU0606, CU0610, CU0625, CU0681, CU0707, CU0737, CU0747, CU0752, CU0761, CU0764, CU0765, CU0767, CU0780, CU0790, CU0799, CU0800, CU0803, CU0811, CU0828, CU
  • C5-interacting compounds of the present disclosure may include any of the compounds listed in Table 3, including SC0001-SC0072 and SC0100- SC0232.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIIa):
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIIa) include SC0001, SC0002, SC0003, SC0004, SC0005, SC0006, SC0007, SC0008, SC0009, SC0010, SC0011, SC0012, SC0013, SC0014, and SC0015.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIIb):
  • R 3 may be any group that has an amide (-CO- NH-) or a phenyl group, wherein each group is optionally further substituted, such as with at least one alkyl group, alkoxyl group, or halogen.
  • R4 may be -H or -OH.
  • R5 may be -CH 3 , - CH 2 OH, or -CH 2 NH 2 , wherein each group is optionally further substituted.
  • R 5 comprises a nitrogen atom and the nitrogen atom may be part of a cyclic or bicyclic structure (saturated or non-saturated).
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIIb) include SC0016, SC0017, SC0018, SC0019, SC0020, SC0021, SC0022, SC0023, SC0024, SC0025, SC0026, SC0027, SC0028, SC0029, SC0030, SC0031, SC0032, SC0033, SC0034, SC0035, SC0036, SC0037, SC0038, SC0039, SC0040, SC0041, SC0042, SC0043, and SC0072.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIIb1):
  • the nitrogen atom may be part of a cyclic or bicyclic structure (saturated or non-saturated).
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIIb1) include SC0016, SC0018, SC0020, SC0021, SC0022, SC0023, SC0024, SC0025, SC0026, SC0027, SC0028, SC0029, SC0030, SC0031, SC0032, SC0033, SC0034, SC0035, SC0036, SC0037, SC0038, SC0039, SC0040, SC0041, SC0042, and SC0043.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIIc):
  • R6 may be an amine group, optionally further substituted with any suitable functional group, such as an alkyl, an alkoxyl, a cyclic group, a heterocyclic group, an aryl group, or a heteroaryl group.
  • the nitrogen in the amine group may be part of a heterocyclic or heteroaryl group.
  • the hetero atom may be nitrogen, sulfur, or oxygen. [0189] In some embodiments, any substituted derivative thereof.
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIIc) include SC0044, SC0045, SC0046, SC0047, SC0048, SC0049, SC0050, and SC0051.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIId):
  • R7 may be an alkyl group, an amide group, a cyclic group, a heterocyclic group, an aryl group, or a heteroaryl group.
  • the hetero atom may be nitrogen, oxygen, or sulfur.
  • Each group may optionally be further substituted with any suitable functional group, such as at least one alkyl, alkoxyl, or halogen.
  • R7 is oxazole, pyridine, pyrazole, or any substituted derivative thereof.
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIId) include SC0052, SC0036, SC0053, SC0054, SC0055, SC0056, and SC0057.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIIe):
  • R 8 may be a phenyl group and may optionally be further substituted, such as with at least one alkyl group, alkoxyl group, or halogen.
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIIe) include SC0058.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIIf):
  • R 9 may be a phenyl group and may optionally be further substituted, such as with at least one alkyl group, alkoxyl group, or halogen.
  • R10 may be an alkyl group, an alkoxyl group, or -OH.
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIIf) include SC0059.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIIg):
  • A may be carbon or oxygen.
  • X1 and X2 may be independently hydrogen, a halogen, an alkyl, or an alkoxyl group.
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIIg) include SC0060, SC0061, and SC0062.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIIg1):
  • B may be carbon or oxygen.
  • X3 and X4 may be independently hydrogen, a halogen, an alkyl, or an alkoxyl group.
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (VIIa) include SC0063.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIIh):
  • R 11 and R 12 may together form a cyclic group, a heterocyclic group, an aryl group, or a heteroaryl group.
  • the hetero atom may be nitrogen, oxygen, or sulfur.
  • Each group may optionally be further substituted with any suitable functional group.
  • Such groups may include at least one -COO-, -SO 2 -, and/or halogen.
  • R 13 may include or a substituted derivative thereof.
  • R13 is
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIIh) include SC0064, SC0065, SC0066, SC0067, SC0068, SC0069, SC0070, and SC0071.
  • a C5 inhibitor compound of the present disclosure has a structure according to Formula (IIIi):
  • X1 is CH or N
  • R1 is H, halogen (such as Cl, F, Br or I), -CN, -CF 3 , or a C 1 -C 3 alkyl group;
  • R2 or R3, independently, is H, alkyl, aryl, heteroaryl, cyclic alkyl, heterocyclic alkyl, a multicyclic alkyl group, or a hetero multicyclic alkyl group, wherein the alkyl, aryl, heteroaryl group, cyclic alkyl, heterocyclic alkyl, multicyclic alkyl, or hetero multicyclic alkyl group is optional substituted; optionally, R2 and R3, together with the nitrogen they are attached, form a 3 to 8 membered heterocyclic group, wherein the heterocyclic group may be optionally substituted; and
  • R4 is H or a C 1 -C 3 alkyl group.
  • R1 is H.
  • R5 is an alkyl group, wherein the alkyl group is optionally substituted.
  • R5 is an alkyl group substituted with an amine group.
  • Non-limiting examples of C5 inhibitor compounds having a structure according to Formula (IIIi) include SC0001, SC0002, SC0003, SC0004, SC0005, SC0006, SC0007, SC0008, SC0009, SC0011, SC0012, SC0014, SC0100, SC0103, SC0105, SC0106, SC0107, SC0108, SC0109, SC0110, SC0111, SC0112, SC0113, SC0117, SC0120, SC0122, SC0124, SC0127, SC0128, SC0129, SC0133, SC0143, SC0147, SC0154, SC0155, SC0156, SC0171, and SC0177.
  • C5 inhibitor compounds of the present disclosure may be directed to chemically stable and feasible compounds.
  • a chemical compound is considered to be feasible and stable when the chemical structure of the compound is not significantly altered when stored at a temperature of 40 °C or less in the absence of chemically reactive conditions, such as moisture for a period of one week.
  • structures presented herein can include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. All stereoisomers, such as enantiomers, diastereomers and geometric isomers are intended unless otherwise indicated. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric and cis/trans mixtures of the present compounds are within the scope of the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • structures presented herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, replacements of a hydrogen atom by deuterium or tritium, or carbon atom by a 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • C5-interacting compounds may be selected based on kinetic and/or thermodynamic solubility.
  • Compound solubility may be an important feature for ease of manufacturing and/or use of compounds in formulations or other therapeutic formats.
  • Thermodynamic solubility refers to the ability of a compound to dissolve in a certain volume of a specific solvent at a given temperature.
  • Kinetic solubility refers to solubility in an aqueous solvent when a compound is added from a high concentration organic solvent stock solution.
  • a kinetic solubility value can be obtained by determining the maximum concentration of dissolved compound that can be achieved in an aqueous solvent when prepared from a high concentration organic solvent (e.g., DMSO).
  • C5-interacting compounds of the present disclosure exhibit a kinetic solubility value of from about 10 mM to about 500 mM, wherein the organic solvent is DMSO and the aqueous solvent is 0.5 M phosphate buffered saline, pH 7.4.
  • the kinetic solubility value may be from about 20 mM to about 50 mM.
  • C5-interacting compounds may be selected based on cell permeability.
  • Cell permeability may be assessed using cell-based permeability assays.
  • Such assays may include the use of cultured cell monolayers on a semi-permeable membrane wherein compounds are introduced to a chamber above or below the cell monolayer and concentration of the compound in a chamber on the opposite side of the cell monolayer is determined over time. Such analysis may be used to calculate an apparent permeability (Papp) value that represents the rate of movement of compound across the cell monolayer.
  • MDCK Madin Darby canine kidney
  • Unidirectional transport may be assessed using MDCK wild type (MDCK-WT) cell monolayers.
  • MDCK-MDR1 cell monolayers may be used.
  • MDCK-MDR1 cells express the MDR1 gene encoding the P-glycoprotein (P-gp) efflux protein.
  • P-gp P-glycoprotein
  • This system may be used to assess bidirectional transport by calculating an efflux ratio for a given compound analyzed. The efflux ratio is determined by obtaining a Papp value for apical to basolateral compound movement (P app A-B) across the MDCK cell monolayer; obtaining a Papp value for basolateral to apical movement (Papp B-A) across the MDCK cell monolayer; and calculating the ratio of Papp A-B to Papp B-A.
  • C5- interacting compounds of the present disclosure exhibit a P app value for movement across MDCK cell monolayers of from about 0.1 x 10 -6 cm/s to about 30 x 10 -6 cm/s, wherein the Papp value is determined by measuring apical to basolateral movement across MDCK cell monolayer.
  • C5-interacting compounds of the present disclosure may exhibit an efflux ratio of from about 5 to about 150, wherein the efflux ratio is determined by obtaining a Papp value for apical to basolateral movement (Papp A-B) across a MDCK-MDR1 cell monolayer; obtaining a Papp value for basolateral to apical movement (Papp B-A) across the MDCK-MDR1 cell monolayer; and calculating the ratio of Papp A-B to Papp B-A.
  • Synthetic reactions may be carried out under various temperatures and/or atmospheric conditions to achieve desired results. Temperatures used in compound synthesis may be varied between -273.16 °C and 150 °C, or greater than 150 °C. In some
  • synthetic reactions are carried out from about -75 °C to about -40 °C, from about -40 °C to about 25 °C, from about 0 °C to about 50 °C, from about 40 °C to about 80 °C, from about 50 °C to about 85 °C, from about 65 °C to about 90 °C, from about 70 °C to about 95 °C, from about 75 °C to about 100 °C, from about 80 °C to about 110 °C, from about 85 °C to about 120 °C, from about 90 °C to about 140 °C, or from about 100 °C to about 150 °C.
  • Atmospheric conditions may be varied to include various levels of gases. Such gases may include, but are not limited to, oxygen, nitrogen, hydrogen, carbon dioxide, and carbon monoxide. Atmospheric conditions may also be varied by pressure to achieve a desired reaction. Atmospheric pressures may be varied, for example, by from about 0 psi to about 1000 psi (e.g., from about 0 psi to about 20 psi, from about 10 psi to about 50 psi, from about 40 psi to about 200 psi, from about 75 psi to about 500 psi, or from about 150 psi to about 1000 psi).
  • gases may include, but are not limited to, oxygen, nitrogen, hydrogen, carbon dioxide, and carbon monoxide.
  • Atmospheric conditions may also be varied by pressure to achieve a desired reaction. Atmospheric pressures may be varied, for example, by from about 0 psi to about 1000 psi (e
  • reactions are carried out under microwave irradiation.
  • Synthetic reactions may be carried out in various reaction mixtures.
  • Reaction mixtures may include water or other solvents. Such solvents may include organic or hydrophobic solvents.
  • Reaction mixtures may be formulated with various compounds to alter one or more of pH and salinity.
  • reaction mixtures may include one or more reaction compounds. Reaction compounds may include reactants, catalysts, and/or other chemicals necessary for facilitating chemical reactions.
  • Chromatography may include, but is not limited to, one or more of thin- layer chromatography (TLC), preparative TLC (prep-TLC), normal phase chromatography, silica gel chromatography, flash silica gel chromatography, high performance liquid chromatography (HPLC), preparative HPLC (prep-HPLC), reverse phase column
  • chromatography and C18 reverse phase HPLC. Filtration may be carried out, in some embodiments, over celite. Removal of water may be carried out, in some embodiments, using a Dean-Stack apparatus.
  • solids may be extracted from solution by lyophilization.
  • preparations may be sonicated before subsequent reactions and/or purification.
  • filtration and/or concentration may be carried out under varying pressure to achieve desired results.
  • filtration, concentration, and/or purification may be carried out in a vacuum.
  • Compound preparations resulting from filtration, concentration, and/or purification may be in liquid or solid form. Liquids preparations may include water or other solvents. Such solvents may include organic solvents or hydrophobic solvents.
  • Some compound preparations may be in the form of an oil.
  • Solid compound preparations may include different formats that include, but are not limited to blocks, crystalline or granular formats, or powders. Filtration, concentration, and/or purification may be carried out using an eluant.
  • Eluants may include water or other solvents. Such solvents may include organic or hydrophobic solvents.
  • Some eluants may include ethyl acetate, petroleum ether, hexane, or n-hexane.
  • Synthesized compounds may be validated for proper structure by methods known to those skilled in the art, for example by nuclear magnetic resonance (NMR) spectroscopy and/or mass spectrometry.
  • NMR nuclear magnetic resonance
  • compounds of the present disclosure may be included in a composition that includes one or more compounds and at least one excipient (e.g., a pharmaceutically acceptable excipient).
  • excipient e.g., a pharmaceutically acceptable excipient
  • Such compositions may include C5 inhibitors.
  • Compounds may be present in compositions at various concentrations, including, but not limited to from about 0.001 mg/mL to about 0.2 mg/mL, from about 0.01 mg/mL to about 2 mg/mL, from about 0.1 mg/mL to about 10 mg/mL, from about 0.5 mg/mL to about 5 mg/mL, from about 1 mg/mL to about 20 mg/mL, from about 15 mg/mL to about 40 mg/mL, from about 25 mg/mL to about 75 mg/mL, from about 50 mg/mL to about 200 mg/mL, or from about 100 mg/mL to about 400 mg/mL.
  • compositions of the present disclosure include aqueous compositions which include at least water and a C5 inhibitor compound.
  • Aqueous C5 inhibitor compositions of the present disclosure may further include one or more salt and/or one or more buffering agent.
  • aqueous compositions of the present disclosure include water, a C5 inhibitor compound, a salt, and a buffering agent.
  • Aqueous C5 inhibitor formulations of the present disclosure may have pH levels of from about 2.0 to about 3.0, from about 2.5 to about 3.5, from about 3.0 to about 4.0, from about 3.5 to about 4.5, from about 4.0 to about 5.0, from about 4.5 to about 5.5, from about 5.0 to about 6.0, from about 5.5 to about 6.5, from about 6.0 to about 7.0, from about 6.5 to about 7.5, from about 7.0 to about 8.0, from about 7.5 to about 8.5, from about 8.0 to about 9.0, from about 8.5 to about 9.5, or from about 9.0 to about 10.0.
  • GMP good manufacturing practice
  • cGMP current GMP
  • FDA US Food and Drug Administration
  • WHO World Health Organization
  • compounds of the present disclosure may be formulated as pharmaceutical compositions.
  • pharmaceutical composition refers to a
  • composition comprising at least one active ingredient (e.g., one or more compounds described herein) in a form and amount that permits the active ingredient to be
  • compounds may be formulated according to any of the techniques for preparing pharmaceutical formulations described in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988- 1999, Marcel Dekker, New York, each of which is incorporated herein by reference.
  • C5 inhibitor compounds may be combined with one or more pharmaceutically acceptable excipient to form a pharmaceutical composition.
  • the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipient refers any ingredient other than the inventive compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, dispensing, or dispersing agents, sweeteners, and waters of hydration.
  • antiadherents antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, dispensing, or dispersing agents, sweeteners, and waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C,
  • compositions comprise one or more active compound ingredients together with ethanol, corn oil-mono-di-triglycerides, hydrogenated castor oil, DL-tocopherol, propylene glycol, gelatin, glycerol, colorants, flavors and sweeteners.
  • methods of the present disclosure include methods of modulating complement activity using C5-interacting compounds described herein. Such methods may include methods of modulating complement activity in biological systems by contacting such systems with C5-interacting compounds.
  • the C5-interacting compounds may be C5 inhibitors disclosed herein.
  • Biological systems may include, but are not limited to, cells, tissues, organs, bodily fluids, organisms, non-mammalian subjects, and mammalian subjects (e.g., humans).
  • the present disclosure provides methods of inhibiting complement activity in a subject.
  • the percentage of complement activity inhibited in a subject may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least, 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%.
  • this level of inhibition and/or maximum inhibition of complement activity may be achieved by from about 1 hour after administration to about 3 hours after administration, from about 2 hours after administration to about 4 hours after administration, from about 3 hours after administration to about 10 hours after administration, from about 5 hours after administration to about 20 hours after administration, or from about 12 hours after administration to about 24 hours after administration.
  • Inhibition of complement activity may continue throughout a period of at least 1 day, of at least 2 days, of at least 3 days, of at least 4 days, of at least 5 days, of at least 6 days, of at least 7 days, of at least 2 weeks, of at least 3 weeks, of at least 4 weeks, of at least 8 weeks, of at least 3 months, of at least 6 months, or at least 1 year. In some cases, this level of inhibition may be achieved through daily
  • Such daily administration may include administration for at least 2 days, for at least 3 days, for at least 4 days, for at least 5 days, for at least 6 days, for at least 7 days, for at least 2 weeks, for at least 3 weeks, for at least 4 weeks, for at least 2 months, for at least 4 months, for at least 6 months, for at least 1 year, or for at least 5 years.
  • subjects may be administered compounds or compositions of the present disclosure for the life of such subjects.
  • compounds of the present disclosure may be used in assays used to assess complement activation and/or inhibition. Some assays may include diagnostic assays. In some cases, compounds may be included in methods of drug discovery. In some embodiments, methods of the present disclosure include use of C5-interacting compounds of the present disclosure to assess C5 binding by other compounds. Such methods may include conjugating C5-interacting compounds with one or more detectable labels (e.g., fluorescent dyes) and measuring C5 dissociation (via detectable label detection) in the presence of the other compounds. The detectable labels may include fluorescent compounds. Therapeutic indications
  • methods of the present disclosure include methods of treating therapeutic indications using compounds and/or compositions disclosed herein.
  • therapeutic indication refers to any symptom, condition, disorder, or disease that may be alleviated, stabilized, improved, cured, or otherwise addressed by some form of treatment or other therapeutic intervention (e.g., through complement inhibitor administration).
  • Therapeutic indications may include, but are not limited to, inflammatory indications, wounds, injuries, autoimmune indications, vascular indications, neurological indications, kidney-related indications, ocular indications, cardiovascular indications, pulmonary indications, and pregnancy-related indications.
  • compositions disclosed herein e.g., complement inhibitor compounds
  • complement inhibitor compounds may be useful in the treatment of complement-related indications where complement activation leads to progression of a disease, disorder and/or condition.
  • complement-related indications may include, but are not limited to inflammatory indications, wounds, injuries, autoimmune indications, vascular indications, neurological indications, kidney-related indications, ocular indications, cardiovascular indications, pulmonary indications, and pregnancy-related indications.
  • Complement-related indications may include, but are not limited to, any of those listed in US Publication No. US2013/091285, the contents of which are herein incorporated by reference in their entirety.
  • Complement inhibitor compounds and compositions may be useful in the treatment of infectious diseases, disorders and/or conditions, for example, in a subject having an infection.
  • subjects having an infection or that are at risk of developing sepsis or a septic syndrome may be treated with complement inhibitors described herein.
  • complement inhibitor compounds may be used in the treatment of sepsis.
  • Complement inhibitor compounds and compositions may also be administered to improve the outcome of clinical procedures wherein complement inhibition is desired. Such procedures may include, but are not limited to grafting, transplantation, implantation, catheterization, intubation and the like.
  • complement inhibitor compounds and compositions are used to coat devices, materials and/or biomaterials used in such procedures.
  • the inner surface of a tube may be coated with compounds and compositions to prevent complement activation within a bodily fluid that passes through the tube, either in vivo or ex vivo, e.g., extracorporeal shunting, e.g., dialysis and cardiac bypass.
  • the terms“treat,”“treatment,” and the like refer to relief from or alleviation of pathological processes.
  • the terms“treat,”“treatment,” and the like mean to relieve or alleviate at least one symptom associated with such condition, or to slow or reverse the progression or anticipated progression of such condition.
  • By“lower” or“reduce” in the context of a disease marker or symptom is meant a significant decrease in such a level, often statistically significant.
  • the decrease may be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and is preferably down to a level accepted as within the range of normal for an individual without such a disorder.
  • By“increase” or“raise” in the context of a disease marker or symptom is meant a significant rise in such level, often statistically significant.
  • the increase may be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and is preferably up to a level accepted as within the range of normal for an individual without such disorder.
  • Efficacy for a given compound or composition may also be judged using an experimental animal model for the given disease as known in the art. When using an experimental animal model, efficacy of treatment is evidenced when a statistically significant modulation in a marker or symptom is observed.
  • Complement-related indications may include paroxysmal nocturnal
  • PNH hemoglobinuria
  • complement inhibitor compounds and compositions may be used to treat, prevent or delay development of PNH.
  • the treatment may be involved with the prevention of hemolysis of PNH erythrocytes in a dose dependent manner.
  • PIG-A phosphatidylinositol glycan anchor biosynthesis, class A (PIG-A) gene that originates from a multipotent hematopoietic stem cell results in a rare disease known as paroxysmal nocturnal hemoglobinuria (PNH) (Pu, J.J. et al., Paroxysmal nocturnal hemoglobinuria from bench to bedside. Clin Transl Sci.2011 Jun;4(3):219-24). PNH is characterized by bone marrow disorder, hemolytic anemia and thrombosis. The PIG- A gene product is necessary for the production of a glycolipid anchor,
  • GPI glycosylphosphatidylinositol
  • CD55 and CD59 become nonfunctional in the absence of GPI. This leads to complement-mediated destruction of these cells.
  • Complement inhibitors are particularly useful in the treatment of PNH.
  • compounds and compositions may be used to treat, prevent or delay development of Paroxysmal nocturnal hemoglobinuria (PNH) or anemias associated with complement.
  • PNH Paroxysmal nocturnal hemoglobinuria
  • Subjects with PNH are unable to synthesize functional versions of the complement regulatory proteins CD55 and CD59 on hematopoietic stem cells. This results in complement-mediated hemolysis and a variety of downstream complications.
  • downstream complication refers to any event occurring after and as a result of another event.
  • downstream events are events occurring after and as a result of C5 cleavage and/or complement activation.
  • PNH is characterized by low hemoglobin, increased levels of lactate
  • Symptoms of PNH include symptoms of anemia, such as tiredness, headaches, dyspnea, chest pain, dizziness, and feeling of lightheadedness.
  • eculizumab may be ineffective due to mutation in C5, short half-life, immune reaction, or other reason.
  • methods of the present disclosure include methods of treating subjects with PNH, wherein such subjects have been treated previously with eculizumab. In some cases, eculizumab is ineffective in such subjects, making treatment with compounds of the present disclosure important for therapeutic relief.
  • compounds of the present disclosure may be used to treat subjects that are resistant to eculizumab treatment. Such subjects may include subjects with the R885H/C polymorphism, which confers resistance to eculizumab.
  • compounds of the present disclosure are administered simultaneously or in conjunction with eculizumab therapy. In such cases, subjects may experience one or more beneficial effects of such combined treatment, including, but not limited to more effective relief, faster relief and/or fewer side effects.
  • compositions of the present disclosure may include inflammatory indications.
  • inflammatory indication refers to therapeutic indications that involve immune system activation.
  • Inflammatory indications may include complement-related indications. Inflammation may be upregulated during the proteolytic cascade of the complement system. Although inflammation may have beneficial effects, excess
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of inflammatory indications.
  • Inflammatory indications may include, but are not limited to, Acute
  • ADAM Disseminated Encephalomyelitis
  • Acute necrotizing hemorrhagic leukoencephalitis Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Acute antibody-mediated rejection following organ transplantation, Anti- GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis,
  • Autoimmune hyperlipidemia Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria, Axonal & neuronal neuropathies, Bacterial sepsis and septic shock, Balo disease, Behcet’s disease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory
  • CIDP demyelinating polyneuropathy
  • CRMO Chronic recurrent multifocal osteomyelitis
  • Churg-Strauss syndrome Cicatricial pemphigoid/benign mucosal pemphigoid, Crohn’s disease
  • Cogans syndrome Cold agglutinin disease
  • Congenital heart block Coxsackie myocarditis
  • CREST disease Essential mixed cryoglobulinemia
  • encephalomyelitis Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with Polyangiitis (GPA) see Wegener's, Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto’s thyroiditis, Hemolytic anemia (including atypical hemolytic uremic syndrome and plasma therapy-resistant atypical hemolytic-uremic syndrome), Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease,
  • Immunoregulatory lipoproteins Inclusion body myositis, Insulin-dependent diabetes (type1), Interstitial cystitis, Juvenile arthritis, Juvenile diabetes, Kawasaki syndrome, Lambert-Eaton syndrome, Large vessel vasculopathy, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, Meniere’s disease, Microscopic polyangiitis, Mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, Multiple endocrine neoplasia syndromes, Multiple sclerosis, Multifocal motor neuropathy, Myositis, Myasthenia gravis, Narcolepsy, Neuromyelitis optica (Devic's), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Osteoarthritis, Palindromic rhe
  • Paroxysmal nocturnal hemoglobinuria PNH
  • Parry Romberg syndrome Parsonnage-Turner syndrome
  • Pars planitis (peripheral uveitis)
  • Pemphigus Peripheral neuropathy
  • Perivenous encephalomyelitis Pernicious anemia
  • POEMS syndrome Polyarteritis nodosa
  • Type I, II, & III autoimmune polyglandular syndromes Polyendocrinopathies, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome,
  • Progesterone dermatitis Primary biliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic Pulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia, Raynauds phenomenon, Reactive arthritis, Reflex sympathetic dystrophy, Reiter’s syndrome, Relapsing polychondritis, Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis,
  • Sympathetic ophthalmia Takayasu’s arteritis, Temporal arteritis/Giant cell arteritis,
  • TTP Thrombocytopenic purpura
  • Tolosa-Hunt syndrome Transverse myelitis
  • Tubular autoimmune disorder Ulcerative colitis
  • Undifferentiated connective tissue disease UCTD
  • Uveitis Uveitis
  • Vesiculobullous dermatosis Vasculitis
  • Vitiligo and Wegener’s granulomatosis (also known as Granulomatosis with Polyangiitis (GPA)).
  • GPA Granulomatosis with Polyangiitis
  • Inflammatory indications may include sterile inflammation.
  • Sterile inflammation is inflammation that occurs in response to stimuli other than infection.
  • Sterile inflammation may be a common response to stress such as genomic stress, hypoxic stress, nutrient stress or endoplasmic reticulum stress caused by a physical, chemical, or metabolic noxious stimuli.
  • Sterile inflammation may contribute to pathogenesis of many diseases such as, but not limited to, ischemia-induced injuries, rheumatoid arthritis, acute lung injuries, drug-induced liver injuries, inflammatory bowel diseases and/or other diseases, disorders or conditions.
  • Mechanism of sterile inflammation and methods and compounds for treatment, prevention and/or delaying of symptoms of sterile inflammation may include any of those taught by Rubartelli et al.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent or delay development of sterile inflammation.
  • SIRS Systemic inflammatory response
  • SIRS systemic inflammatory response syndrome
  • SIRS is inflammation affecting the whole body. Where SIRS is caused by an infection, it is referred to as sepsis. SIRS may also be caused by non-infectious events such as trauma, injury, burns, ischemia, hemorrhage and/or other conditions.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat and/or prevent SIRS.
  • Complement inhibitor compounds and compositions may be used to control and/or balance complement activation for prevention and treatment of SIRS, sepsis and/or MOF.
  • the methods of applying complement inhibitors to treat SIRS and sepsis may include those taught by Rittirsch et al. in Clin Dev Immunol, 2012, 962927, in U.S.
  • ARDS Acute respiratory distress syndrome
  • Inflammatory indications may include acute respiratory distress syndrome (ARDS).
  • ARDS is a widespread inflammation of the lungs and may be caused by trauma, infection (e.g., sepsis), severe pneumonia and/or inhalation of harmful substances.
  • ARDS is typically a severe, life-threatening complication.
  • neutrophils may contribute to development of ARDS by affecting the accumulation of polymorphonuclear cells in the injured pulmonary alveoli and interstitial tissue of the lungs.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat and/or prevent development of ARDS.
  • Complement inhibitor compounds and compositions may be administered to reduce and/or prevent tissue factor production in alveolar neutrophils.
  • Complement inhibitor compounds and compositions may further be used for treatment, prevention and/or delaying of ARDS, in some cases according to any of the methods taught in International publication No. WO2009/014633, the contents of which are herein incorporated by reference in their entirety.
  • Periodontitis may include periodontitis.
  • Periodontitis is a widespread, chronic inflammation leading to the destruction of periodontal tissue which is the tissue supporting and surrounding the teeth. The condition also involves alveolar bone loss (bone that holds the teeth).
  • Periodontitis may be caused by a lack of oral hygiene leading to accumulation of bacteria at the gum line, also known as dental plaque.
  • Certain health conditions such as diabetes or malnutrition and/or habits such as smoking may increase the risk of periodontitis.
  • Periodontitis may increase the risk of stroke, myocardial infarction, atherosclerosis, diabetes, osteoporosis, pre-term labor, as well as other health issues. Studies demonstrate a correlation between periodontitis and local complement activity.
  • Periodontal bacteria may either inhibit or activate certain components of the complement cascade.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat or prevent development of periodontitis and/or associated conditions.
  • Complement activation inhibitors and treatment methods may include any of those taught by Hajishengallis in Biochem Pharmacol.2010, 15; 80(12): 1 and Lambris or in US publication No. US2013/0344082, the contents of each of which are herein incorporated by reference in their entirety.
  • Inflammatory indications may include dermatomyositis. Dermatomyositis is an inflammatory myopathy characterized by muscle weakness and chronic muscle
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of dermatomyositis.
  • Inflammatory indications may include rheumatoid arthritis.
  • Rheumatoid arthritis is an autoimmune condition affecting the wrists and small joints of the hands. Typical symptoms include pain, stiffness of the joints, swelling, and feeling of warmth.
  • Activated components of the complement system affect development of rheumatoid arthritis, as products of complement cascade mediate proinflammatory activities, such as vascular permeability and tone, leukocyte chemotaxis and the activation and lysis of multiple cell types (see Wang, et al., Proc. Natl. Acad. Sci., 1995; 92: 8955-8959). Wang et al.
  • Complement activation inhibitors and treatment methods may include any of those taught by Wang, et al., Proc. Natl. Acad.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat or prevent development of rheumatoid arthritis.
  • Inflammatory indications may include asthma.
  • Asthma is a chronic inflammation of the bronchial tubes, which are the airways allowing air to pass in and out of the lungs. The condition is characterized by narrowing, inflammation and hyperresponsiveness of the tubes. Typical symptoms include periods of wheezing, chest tightness, coughing and shortness of breath. Asthma the most common respiratory disorder.
  • Complement proteins C3 and C5 are associated with many pathophysiological features of asthma, such as inflammatory cell infiltration, mucus secretion, increased vascular permeability, and smooth muscle cell contraction, and therefore it has been suggested that downregulation of complement activation may be used to treat, manage or prevent asthma.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of asthma.
  • Complement activation inhibitors and treatment methods may include any of those taught by Khan et al., Respir Med.2014 April ; 108(4): 543–549, the contents of which are herein incorporated by reference in their entirety. Anaphylaxis
  • Inflammatory indications may include anaphylaxis.
  • Anaphylaxis is a severe and potentially life-threatening allergic reaction. Anaphylaxis may lead to a shock characterized e.g. by sudden drop of blood pressure, narrowing of airways, breathing difficulties, rapid and weak pulse, a rash, nausea and vomiting. The cardiopulmonary collapse during anaphylaxis has been associated with complement activation and generation of C3a and C5a
  • Complement activation inhibitors and treatment methods may include any of those taught by Balzo et al., the contents of which are herein incorporated by reference in their entirety.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of anaphylaxis. Bowel inflammation
  • IBD inflammatory bowel disease
  • IBD is a reoccurring condition with periods of mild to severe inflammation or periods of remission. Common symptoms include diarrhea, fatigue and fever, abdominal pain, weight loss, reduced appetite and bloody stool. Types of IBD include ulcerative proctitis, dextran sulfate sodium colitis, proctosigmoitidis, left-sided colitis, panconlitis, acute severe ulcerative colitis.
  • IBD such as dextran sulfate sodium colitis and ulcerative colitis
  • Complement activation inhibitors and treatment methods may include any of those taught by Webb et al. or Aomatsu et al, the contents of each of which are herein incorporated by reference in their entirety.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of IBD.
  • Inflammatory indications may include inflammatory response induced by cardiopulmonary bypass (CBP).
  • CBP is a technique used during surgery to take over the function of heart and lungs to maintain blood circulation and oxygen concentration of the blood.
  • CBD provokes a systemic inflammatory response that may lead to complications of the surgical patients.
  • the suggested cause may be due to contact activation of blood with artificial surfaces during extracorporeal circulation.
  • the inflammation response may lead to SIRS and be life-threatening.
  • Complement activation has been associated with the inflammatory response induced by CBP.
  • Complement activation inhibitors and treatment methods may include any of those taught by Rinder et al. J Clin Invest.1995; 96(3): 1564–1572, the contents of which are herein incorporated by reference in their entirety.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of inflammatory response induced by CBP.
  • Inflammatory indications may include immune rejection of transplants.
  • Transplants may be organs (e.g. heart, kidneys, liver, lungs, intestine, thymus and pancreas) or tissues (e.g. bones, tendons, skin, cornea, veins).
  • organs e.g. heart, kidneys, liver, lungs, intestine, thymus and pancreas
  • tissues e.g. bones, tendons, skin, cornea, veins.
  • autograft transplanting patient’s own tissue
  • allograft transplant between two members of the same species
  • xenograft transplant between members of different species, e.g. from an animal to a human.
  • Complications after organ transplant arise as the recipient’s immune system attacks the transplanted tissue.
  • the rejection may be hyperacute referring to a reaction occurring within few minutes after the transplant is performed, and typically occurs when the antigens are unmatched.
  • Acute rejection occurs within a week or few months after transplant. Some rejections are chronic and take place over many years.
  • the complement cascade is relevant to transplantation in a number of ways, e.g. as an effector mechanism of antibody-initiated allograft injury, promotion of ischemia-reperfusion injury, and formation and function of alloantibodies (Sheen and Heeger, Curr Opin Organ Transplant.2015;20(4):468-75).
  • C5 blockage of C5 with eculizumab reduces the incidence of early antibody-mediated rejection (AMR) of organ allografts (Stegall et al., Nature Reviews Nephrology 8(11):670-8, 2012) and inhibition of C5 may prevent acute cardiac tissue injury in an ex vivo model of pig-to-human xenotransplantation (Kroshus et al, Transplantation.1995,15;60(11):1194-202.)
  • Complement activation inhibitors and treatment methods may include any of those taught by Stegall et al., Nature Reviews Nephrology 8(11):670-8, 2012 and Kroshus et al, Transplantation.1995,15;60(11):1194-202, and (Sheen and Heeger, Curr Opin Organ Transplant.2015;20(4):468-75, the contents of each of which are herein incorporated by reference in their entirety
  • compositions of the present disclosure may include wounds and injuries.
  • injury typically refers to physical trauma, but may include localized infection or disease processes. Injuries may be characterized by harm, damage or destruction caused by external events affecting body parts and/or organs. Non-limiting examples of injuries include head trauma and crush injuries. Wounds are associated with cuts, blows, burns and/or other impacts to the skin, leaving the skin broken or damaged. Wounds and injuries may include complement-related indications. Wounds and injuries are often acute but if not healed properly they may lead to chronic complications and/or inflammation. In some embodiments, complement inhibitor compounds and compositions of the present disclosure may be used to treat and/or promote healing of different types of wounds and/or injuries.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat and/or to promote healing of wounds.
  • Healthy skin provides a waterproof, protective barrier against pathogens and other environmental effectors.
  • the skin also controls body temperature and fluid evaporation. When skin is wounded these functions are disrupted making skin healing challenging. Wounding initiates a set of physiological processes related to the immune system that repair and regenerate tissue. Complement activation is one of these processes. Complement activation studies have identified several complement components involved with wound healing as taught by van de Goot et al. in J Burn Care Res 2009, 30:274–280 and Cazander et al.
  • complement activation may be excessive, causing cell death and enhanced inflammation (leading to impaired wound healing and chronic wounds).
  • complement inhibitor compounds and compositions may be used to reduce or eliminate such complement activation to promote wound healing. Treatment with
  • complement inhibitor compounds and compositions may be carried out according to any of the methods for treating wounds disclosed in International Publication No. WO2012/174055, the contents of which are herein incorporated by reference in their entirety.
  • Wounds and/or injuries may include head trauma.
  • Head traumas include injuries to the scalp, the skull or the brain. Examples of head trauma include, but are not limited to concussions, contusions, skull fracture, traumatic brain injuries and/or other injuries. Head traumas may be minor or severe. In some cases, head trauma may lead to long term physical and/or mental complications or death. Studies indicate that head traumas may induce improper intracranial complement cascade activation, which may lead to local inflammatory responses contributing to secondary brain damage by development of brain edema and/or neuronal death (Stahel et al. in Brain Research Reviews, 1998, 27: 243–56, the contents of which are herein incorporated by reference in their entirety).
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat head trauma and/or prevent or delay development of diseases, disorders, and/or conditions associated with head trauma.
  • complement inhibitor compounds and compositions may be used to treat, prevent, reduce, or delay development of secondary complications of head trauma.
  • Methods of using complement inhibitor compounds and compositions to control complement cascade activation in head trauma may include any of those taught by Holers et al. in United States Patent No.8,911,733, the contents of which are herein incorporated by reference in their entirety.
  • Wounds and/or injuries may include crush injuries.
  • Crush injuries are injuries caused by a force or a pressure put on the body causing bleeding, bruising, fractures, nerve injuries, wounds and/or other damages to the body.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat and/or promote healing of crush injuries. Treatment may be used to reduce complement activation following crush injuries, thereby promoting healing after crush injuries (e.g., by promoting nerve regeneration, promoting fracture healing, preventing or treating inflammation, and/or other related complications).
  • Complement inhibitor compounds and compositions may be used to promote healing according to any of the methods taught in United States Patent No. 8,703,136; International Publication Nos. WO2012/162215; WO2012/174055; or US publication No. US2006/0270590, the contents of each of which are herein incorporated by reference in their entirety.
  • Therapeutic indications addressed with compounds and/or compositions of the present disclosure may include autoimmune indications.
  • the term autoimmune indications As used herein, the term
  • autoimmune indication refers to any therapeutic indication relating to immune targeting of a subject’s tissues and/or substances by the subject’s own immune system.
  • Autoimmune indications may include complement-related indications. Autoimmune indications may involve certain tissues or organs of the body.
  • the immune system may be divided into innate and adaptive systems, referring to nonspecific immediate defense mechanisms and more complex antigen-specific systems, respectively.
  • the complement system is part of the innate immune system, recognizing and eliminating pathogens. Additionally, complement proteins may modulate adaptive immunity, connecting innate and adaptive responses.
  • Complement inhibitor compounds and compositions of the present disclosure may be used to modulate complement in the treatment and/or prevention of autoimmune diseases. In some cases, such compounds and compositions may be used according to the methods presented in Ballanti et al. Immunol Res (2013) 56:477–491, the contents of which are herein incorporated by reference in their entirety.
  • autoimmune indications include myasthenia gravis.
  • APS Anti-phospholipid syndrome
  • CAPS catastrophic anti-phospholipid syndrome
  • Autoimmune indications may include anti-phospholipid syndrome (APS).
  • APS is an autoimmune condition caused by anti-phospholipid antibodies that cause the blood to clot. APS may lead to recurrent venous or arterial thrombosis in organs, and complications in placental circulations causing pregnancy-related complications such as miscarriage, still birth, preeclampsia, premature birth and/or other complications.
  • Catastrophic anti- phospholipid syndrome (CAPS) is an extreme and acute version of a similar condition leading to occlusion of veins in several organs simultaneously. Studies suggest that complement activation may contribute to APS-related complications including pregnancy- related complications, thrombotic (clotting) complications, and vascular complications.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of APS and/or APS-related complications.
  • complement inhibitor compounds and compositions of the present disclosure may be used to prevent and/or treat APS by complement activation control.
  • complement inhibitor compounds and compositions may be used to treat APS and/or APS-related complications according to the methods taught by Salmon et al. Ann Rheum Dis 2002;61(Suppl II):ii46–ii50 and Mackworth-Young in Clin Exp Immunol 2004, 136:393–401, the contents of which are herein incorporated by reference in their entirety.
  • CAD cold agglutinin disease
  • CAD is an autoimmune disease resulting from a high concentration of IgM antibodies interacting with red blood cells at low range body temperatures (Engelhardt et al. Blood, 2002, 100(5):1922-23). CAD may lead to conditions such as anemia, fatigue, dyspnea, hemoglobinuria and/or acrocyanosis. CAD is related to robust complement activation and studies have shown that CAD may be treated with complement inhibitor therapies. In some embodiments, complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay
  • complement inhibitor compounds and compositions may be used to treat CAD according to the methods taught by Roth et al in Blood, 2009, 113:3885-86 or in
  • Autoimmune indications may include dermatological disease. Skin has a role in a spectrum of immunological reactions and are associated with abnormal or overactivated complement protein functions. Autoimmune mechanisms with autoantibodies and cytotoxic functions of the complement affect epidermal or vascular cells causing tissue damage and skin inflammation (Palenius and Meri, Front Med (Lausanne).2015; 2: 3). Dermatological diseases associated with autoimmune and complement abnormality include, but are not limited to, hereditary and acquired angioedema, autoimmune urticarial (hives), systemic lupus erythematosus, vasculitis syndromes and urticarial vasculitis, bullous skin diseases (e.g. pemphigus, bullous pemphigioid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, dermatitis herpetiformis, pemphigoides festationis), and partial
  • complement inhibitor compounds and compositions may be used to treat autoimmune dermatological diseases according to the methods taught by Palenius and Meri, Front Med (Lausanne).2015; 2: 3, the contents of which are herein incorporated by reference in their entirety.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of dermatological diseases.
  • Therapeutic indications addressed with compounds and/or compositions of the present disclosure may include pulmonary indications.
  • pulmonary indication refers to any therapeutic indication related to the lungs and/or related airways.
  • Pulmonary indications may include complement-related indications. Pulmonary indications may include, but are not limited to, asthma, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of pulmonary indications.
  • COPD Chronic obstructive pulmonary disease
  • Pulmonary indications may include chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • COPD refers to a class of disorders related to progressive lung dysfunction. They are most often characterized by breathlessness. Complement dysfunction has been indicated as a contributor to some pulmonary indications related to COPD (Pandya, P.H. et al.2013. Translational Review.51(4): 467-73, the contents of which are herein incorporated by reference in their entirety).
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of COPD.
  • Therapeutic indications addressed with compounds and/or compositions of the present disclosure may include cardiovascular indications.
  • cardiovascular indications refers to any therapeutic indication relating to the heart and/or vasculature. Cardiovascular indications may include complement-related indications.
  • Cardiovascular indications may include, but are not limited to, atherosclerosis, myocardial infarction, stroke, vasculitis, trauma and conditions arising from cardiovascular intervention (including, but not limited to cardiac bypass surgery, arterial grafting and angioplasty).
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of cardiovascular indications.
  • Vascular indications are cardiovascular indications related to blood vessels (e.g., arteries, veins, and capillaries). Such indications may affect blood circulation, blood pressure, blood flow, organ function, and/or other bodily functions.
  • blood vessels e.g., arteries, veins, and capillaries.
  • Such indications may affect blood circulation, blood pressure, blood flow, organ function, and/or other bodily functions.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of vascular indications.
  • cardiovascular indications include therapeutic indications associated with coagulation, the coagulation cascade, and/or coagulation cascade
  • Coagulation and complement are coordinately activated in an overlapping spatiotemporal manner in response to common pathophysiologic stimuli to maintain homeostasis.
  • Disease may emerge with unchecked activation of the innate immune and coagulation responses. Examples include, for example, atherosclerosis, stroke, coronary heart disease, diabetes, ischemia-reperfusion injury, trauma, paroxysmal nocturnal
  • hemoglobinuria age-related macular degeneration, and atypical hemolytic-uremic syndrome.
  • thrombin was found to promote complement activation by cleaving C5 (Huber-Lang, et al., 2006. Nature Med.12(6):682-687; the contents of which are herein incorporated by reference in their entirety). While thrombin is capable of cleaving C5 at R751 (yielding C5a and C5b), it more efficiently cleaves C5 at a highly conserved R947 site, generating C5T and C5bT intermediates. C5bT interacts with other complement proteins to form the C5b T -9 membrane attack complex with significantly more lytic activity than with C5b-9 (Krisinger, et al., (2014). Blood.120(8):1717-1725).
  • Complement may be activated by additional components of the coagulation and/or inflammation cascades.
  • additional components of the coagulation and/or inflammation cascades For example, other serine proteases with slightly different substrate specificity may act in a similar way. Huber-Lang et al. (2006) showed that thrombin not only cleaved C5 but also generated C3a in vitro when incubated with native C3 (Huber-Lang, et al., 2006. Nature Med.12(6):682-687).
  • other components of the coagulation pathway such as FXa, FXIa and plasmin, have been found to cleave both C5 and C3.
  • compounds and compositions of the present disclosure may be used to treat cardiovascular indications related to coagulation, the coagulation cascade, and/or coagulation cascade components.
  • the coagulation cascade components may include, but are not limited to, tissue factor, thrombin, FXa, FIXa, FXIa, plasmin, or other coagulation proteases.
  • Compounds and/or compositions of the present disclosure may be used to treat complement activity and/or coagulation (e.g., thrombosis) associated with such
  • TMA Thrombotic microangiopathy
  • Vascular indications may include thrombotic microangiopathy (TMA) and associated diseases.
  • TMA thrombotic microangiopathy
  • Microangiopathies affect small blood vessels (capillaries) of the body causing capillary walls to become thick, weak, and prone to bleeding and slow blood circulation.
  • TMAs tend to lead to the development of vascular thrombi, endothelial cell damage, thrombocytopenia, and hemolysis.
  • Organs such as the brain, kidney, muscles, gastrointestinal system, skin, and lungs may be affected.
  • TMAs may arise from medical operations and/or conditions that include, but are not limited to, hematopoietic stem cell transplantation (HSCT), renal disorders, diabetes and/or other conditions.
  • HSCT hematopoietic stem cell transplantation
  • TMAs may be caused by underlying complement system dysfunction, as described by Meri et al. in
  • TMAs may result from increased levels of certain complement components leading to thrombosis. In some cases, this may be caused by mutations in complement proteins or related enzymes. Resulting complement dysfunction may lead to complement targeting of endothelial cells and platelets leading to increased thrombosis.
  • TMAs may be prevented and/or treated with complement inhibitor compounds and compositions of the present disclosure. In some cases, methods of treating TMAs with complement inhibitor compounds and compositions may be carried out according to those described in US publication Nos. US2012/0225056 or US2013/0246083, the contents of each of which are herein incorporated by reference in their entirety.
  • DIC disseminated intravascular coagulation
  • DIC is a pathological condition where the clotting cascade in blood is widely activated and results in formation of blood clots especially in the capillaries.
  • DIC may lead to an obstructed blood flow of tissues and may eventually damage organs. Additionally, DIC affects the normal process of blood clotting that may lead to severe bleeding.
  • Complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent or reduce the severity of DIC by modulating complement activity. In some cases, complement inhibitor compounds and compositions may be used according to any of the methods of DIC treatment taught in US Patent No.8,652,477, the contents of which are herein incorporated by reference in their entirety.
  • Vascular indications may include vasculitis.
  • vasculitis is a disorder related to inflammation of blood vessels, including veins and arteries, characterized by white blood cells attacking tissues and causing swelling of the blood vessels.
  • Vasculitis may be associated with an infection, such as in Rocky Mountain spotted fever, or autoimmunity.
  • An example of autoimmunity associated vasculitis is Anti-Neutrophil Cytoplasmic Autoantibody (ANCA) vasculitis.
  • ANCA vasculitis is caused by abnormal antibodies attacking the body’s own cells and tissues. ANCAs attack the cytoplasm of certain white blood cells and neutrophils, causing them to attack the walls of the vessels in certain organs and tissues of the body.
  • ANCA vasculitis may affect skin, lungs, eyes and/or kidney. Studies suggest that ANCA disease activates an alternative complement pathway and generates certain complement components that create an inflammation amplification loop resulting in a vascular injury (Jennette et al.2013, Semin Nephrol.33(6): 557-64, the contents of which are herein incorporated by reference in their entirety).
  • complement inhibitor compounds and compositions of the present disclosure may be used to prevent and/or treat vasculitis.
  • complement inhibitor compounds and compositions may be used to prevent and/or treat ANCA vasculitis by inhibiting complement activation. Neurological indications
  • Therapeutic indications addressed with compounds and/or compositions of the present disclosure may include neurological indications.
  • Neurological indication refers to any therapeutic indication relating to the nervous system.
  • Neurological indications may include complement-related indications.
  • Neurological indications may include neurodegeneration. Neurodegeneration generally relates to a loss of structure or function of neurons, including death of neurons.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of neurological indications, including, but not limited to neurodegenerative diseases and related disorders. Treatment may include inhibiting the effect of complement activity on neuronal cells using compounds and compositions of the present disclosure.
  • Neurodegenerative related disorders include, but are not limited to,
  • ALS Amyelotrophic Lateral Sclerosis
  • MS Multiple Sclerosis
  • Parkinson's disease Alzheimer's disease
  • Lewy body dementia Lewy body dementia.
  • complement-related neurological indications include myasthenia gravis.
  • ALS Amyotrophic lateral sclerosis
  • Neurological indications may include ALS.
  • ALS is a fatal motor neuron disease characterized by the degeneration of spinal cord neurons, brainstems and motor cortex. ALS causes loss of muscle strength leading eventually to a respiratory failure. Complement dysfunction may contribute to ALS, and therefore ALS may be prevented, treated and/or the symptoms may be reduced by therapy with complement inhibitor compounds and
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of ALS and/or promote nerve regeneration.
  • complement inhibitor compounds and compositions may be used as complement inhibitors according to any of the methods taught in US publication No. US2014/0234275 or US2010/0143344, the contents of each of which are herein incorporated by reference in their entirety.
  • Neurological indications may include Alzheimer’s disease.
  • Alzheimer’s disease is a chronic neurodegenerative disease with symptoms that may include disorientation, memory loss, mood swings, behavioral problems and eventually loss of bodily functions.
  • Alzheimer’s disease is thought to be caused by extracellular brain deposits of amyloid that are associated with inflammation-related proteins such as complement proteins (Sjoberg et al.2009. Trends in Immunology.30(2): 83-90, the contents of which are herein incorporated by reference in their entirety).
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of Alzheimer’s disease by controlling complement activity.
  • complement inhibitor compounds and compositions may be used according to any of the Alzheimer’s treatment methods taught in US publication No. US2014/0234275, the contents of which are herein incorporated by reference in their entirety.
  • Neurological indications may include multiple sclerosis (MS) or neuromyelitis optica (NMO).
  • MS is an inflammatory condition affecting the central nervous system as the immune system launches an attack against the body’s own tissues, and in particular against nerve-insulating myelin. The condition may be triggered by an unknown environmental agent, such as a virus.
  • MS is progressive and eventually results in disruption of the communication between the brain and other parts of the body. Typical early symptoms include blurred vision, partial blindness, muscle weakness, difficulties in coordination and balance, impaired movement, pain and speech impediments.
  • NMO also known as Devic’s disease
  • Typical symptoms of NMO include muscle weakness of the legs or paralysis, loss of senses (e.g. blindness) and dysfunctions of the bladder and bowel.
  • MS and NMO have been associated with complement component regulation e.g. by pathological and animal model studies (Ingram et al., Clin Exp Immunol.2009 Feb;
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of MS or NMO. Treatment methods may include any of those taught by Ingram et al., Clin Exp Immunol.2009 Feb; 155(2): 128–139, the contents of which are herein incorporated by reference in their entirety.
  • Neurological indications may include myasthenia gravis.
  • Myasthenia gravis is a rare complement-mediated autoimmune disease characterized by the production of autoantibodies targeting proteins that are critical for the normal transmission of chemical or neurotransmitter signals from nerves to muscles, e.g., acetylcholine receptor (AChR) proteins.
  • AChR acetylcholine receptor
  • the term“MG” embraces any form of MG. While about 15% of patients have symptoms that are confined to ocular muscles, the majority of patients experience generalized myasthenia gravis.
  • the term“generalized myasthenia gravis” or“gMG” refers to MG that affects multiple muscle groups throughout the body. Although the prognosis of MG is generally benign, 10% to 15% of patients have refractory MG. As used herein, the term“refractory MG” or“rMG” refers to MG where disease control either cannot be achieved with current therapies, or results in severe side effects of immunosuppressive therapy. This severe form of MG affects approximately 9,000 individuals in the United States.
  • Muscle weakness can be localized to specific muscles, such as those responsible for eye movements, but often progresses to more diffuse muscle weakness. MG may even become life-threatening when muscle weakness involves the diaphragm and the other chest wall muscles responsible for breathing. This is the most feared complication of MG, known as myasthenic crisis or MG crisis, and requires hospitalization, intubation, and mechanical ventilation. Approximately 15% to 20% of patients with gMG experience a myasthenic crisis within two years of diagnosis.
  • AChR acetylcholine receptor
  • Current therapies for gMG focus on either augmenting the AChR signal or nonspecifically suppressing the autoimmune response.
  • First-line therapy for symptomatic gMG is treatment with acetylcholinesterase inhibitors such as pyridostigmine, which is the only approved therapy for MG.
  • pyridostigmine monotherapy is usually insufficient for the treatment of generalized weakness, and dosing of this therapy may be limited by cholinergic side effects.
  • immunosuppressive therapy has been approved for the treatment of gMG. Moreover, all of these agents are associated with well-documented long-term toxicities. Surgical removal of the thymus may be recommended in patients with nonthymomatous gMG and moderate to severe symptoms in an effort to reduce the production of AChR autoantibodies (Wolfe GI, et al.2016. N Engl J Med.375(6):511-22). Intravenous (IV) immunoglobulin and plasma exchange are usually restricted to short-term use in patients with myasthenic crisis or life- threatening signs such as respiratory insufficiency or dysphagia (Sanders et al., 2016).
  • Binding of anti-AChR autoantibodies to the muscle endplate results in activation of the classical complement cascade and deposition of MAC on the post-synaptic muscle fiber leading to local damage to the muscle membrane, and reduced responsiveness of the muscle to stimulation by the neuron.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of MG (e.g., gMG and/or rMG). Inhibition of complement activity may be used to block complement-mediated damage resulting from MG (e.g., gMG and/or rMG).
  • kidney-related indications may include kidney-related indications.
  • kidney-related indications may include complement-related indications.
  • Kidneys are organs responsible for removing metabolic waste products from the blood stream. Kidneys regulate blood pressure, the urinary system, and homeostatic functions and are therefore essential for a variety of bodily functions. Kidneys may be more seriously affected by inflammation (as compared to other organs) due to unique structural features and exposure to blood. Kidneys also produce their own complement proteins which may be activated upon infection, kidney disease, and renal transplantations.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of kidney-related indications, in some cases by inhibiting complement activity.
  • complement inhibitor compounds and compositions may be used to treat kidney-related indications according to the methods taught by Quigg, J Immunol 2003; 171:3319-24, the contents of which are herein incorporated by reference in their entirety.
  • Atypical hemolytic uremic syndrome (aHUS)
  • Kidney-related indications may include atypical hemolytic uremic syndrome (aHUS).
  • aHUS belongs to the spectrum of thrombotic microangiopathies.
  • aHUS is a condition causing abnormal blood clots formation in small blood vessels of the kidneys. The condition is commonly characterized by hemolytic anemia, thrombocytopenia and kidney failure, and leads to end-stage renal disease (ESRD) in about half of all cases.
  • ESRD end-stage renal disease
  • aHUS has been associated with abnormalities of the alternative pathway of the complement system and may be caused by a genetic mutation in one of the genes that lead to increased activation of the alternative pathway.
  • aHUS may be treated by inhibitors that control the alternative pathway of complement activation, including C5 activation.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent or delay development of aHUS.
  • Methods and compositions for preventing and/or treating aHUS by complement inhibition may include any of those taught by Verhave et al. in Nephrol Dial Transplant. 2014;29 Suppl 4:iv131-41 or International Publication WO 2016/138520, the contents of each of which are herein incorporated by reference in their entirety.
  • Kidney-related indications may include lupus nephritis.
  • Lupus nephritis is a kidney inflammation caused by an autoimmune disease called systemic lupus erythematosus (SLE).
  • SLE systemic lupus erythematosus
  • Symptoms of lupus nephritis include high blood pressure; foamy urine; swelling of the legs, the feet, the hands, or the face; joint pain; muscle pain; fever; and rash.
  • SLE systemic lupus erythematosus
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of lupus nephritis, in some cases through complement activity inhibition.
  • Related methods may include any of those taught in US publication No. US2013/0345257 or United States Patent No.8,377,437, the contents of each of which are herein incorporated by reference in their entirety.
  • Kidney-related indications may include membranous glomerulonephritis (MGN).
  • MGN is a disorder of the kidney that may lead to inflammation and structural changes. MGN is caused by antibodies binding to a soluble antigen in kidney capillaries (glomerulus). MGN may affect kidney functions, such as filtering fluids and may lead to kidney failure.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of MGN, including by inhibiting complement activity.
  • Related treatment methods may include any of those taught in U.S. publication No. US2010/0015139 or in International publication No. WO2000/021559, the contents of each of which are herein incorporated by reference in their entirety.
  • Kidney-related indications may include hemodialysis complications.
  • Hemodialysis is a medical procedure used to maintain kidney function in subjects with kidney failure. In hemodialysis, the removal of waste products such as creatinine, urea, and free water from blood is performed externally.
  • a common complication of hemodialysis treatment is chronic inflammation caused by contact between blood and the dialysis membrane.
  • Another common complication is thrombosis referring to a formation of blood clots that obstructs the blood circulation. Studies have suggested that these complications are related to complement activation.
  • Hemodialysis may be combined with complement inhibitor therapy to provide means of controlling inflammatory responses and pathologies and/or preventing or treating thrombosis in subjects going through hemodialysis due to kidney failure. In some
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of hemodialysis complications, including by inhibiting complement activation.
  • Related methods for treatment of hemodialysis complications may include any of those taught by DeAngelis et al in Immunobiology, 2012, 217(11): 1097–1105 or by Kourtzelis et al. Blood, 2010, 116(4):631-639, the contents of each of which are herein incorporated by reference in their entirety.
  • Kidney-related indications may include IgA nephropathy.
  • IgA nephropathy is the most common cause of glomerulonephritis, affecting 25 in every one million per year. The disease is characterized by mesangial deposits of IgA and complement components in the glomeruli.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of IgA nephropathy by inhibiting the activation of certain complement components.
  • compositions of the invention may be used according to methods of preventing and/or treating IgA nephropathy by complement inhibition taught by Maillard N et al., in J of Am Soc Neph (2015) 26(7):1503-1512, the contents of each of which are herein incorporated by reference in their entirety
  • Kidney-related indications may include dense deposit disease
  • DDD Dense deposit disease
  • DDD Dense deposit disease
  • C3 glomerulonephritis type II, and C3 glomerulopathy Dense deposit disease
  • DDD Dense deposit disease
  • C3 CFH proteinuria, hematuria, reduced amounts of urine, low levels of protein in the blood, and swelling in many areas of the body.
  • DDD can be caused by mutations in the C3 and CFH genes; by both genetic risk factors and environmental triggers; or by the presence of autoantibodies blocking the activity of proteins needed for the body's immune response.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of DDD. Such uses may include reducing and/or blocking complement alternative pathway activity. Such methods may prevent glomerular C3 deposition.
  • Kidney-related indications may include focal-segmental glomerulosclerosis.
  • Focal- segmental glomerulosclerosis (FSGS) is a common cause of glomerular disease in children and adults and most commonly presents as severe nephrotic syndrome. Diagnosis of FSGS is made based on histopathological findings and exclusion of other diagnoses common in nephrotic syndrome. Many patients will have substantial deposition of IgM and C3 in sclerotic regions on biopsy. Additionally, biomarkers for complement activation (factor B fragments, C 4 a, soluble MAC) have been detected in plasma and urine from patients with FSGS, with levels of Ba and Bb correlating with disease severity (J. Thurman et al,
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of FSGS.
  • Therapeutic indications addressed with compounds and/or compositions of the present disclosure may include diabetes-related indications.
  • diabetes-related indications refers to any therapeutic indication resulting from or relating to elevated blood sugar.
  • Diabetes-related indications may include complement-related indications. Diabetes-related indications may occur as a result of organ and/or tissue exposure to prolonged hyperglycemia. Prolonged hyperglycemia can result in glycation inactivation of the membrane-associated complement regulatory protein CD59, leaving certain cells and tissues susceptible to complement attack (P. Ghosh et al, 2015. Endocrine Reviews, 36 (3), 2015).
  • Complement-mediated complications from diabetes may include, but are not limited to, diabetic neuropathy, diabetic nephropathy, diabetic cardiovascular disease, and complications resulting from gestational diabetes such as high or low birth weight and resulting complications.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay
  • Such uses may include addressing diabetes-related indications through complement activity inhibition.
  • Therapeutic indications addressed with compounds and/or compositions of the present disclosure may include ocular indications.
  • Ocular indications refers to any therapeutic indication relating to the eye.
  • Ocular indications may include complement-related indications.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of ocular indications, including by inhibiting complement activity.
  • Related treatment methods may include any of those taught by Jha et al. in Mol Immunol.2007; 44(16): 3901–3908 or in US Patent No.8,753,625, the contents of each of which are herein incorporated by reference in their entirety.
  • Ocular indications may include, but are not limited to, age-related macular degeneration, allergic and giant papillary conjunctivitis, Behcet's disease, choroidal inflammation, complications related to intraocular surgery, corneal transplant rejection, corneal ulcers, cytomegalovirus retinitis, dry eye syndrome, endophthalmitis, Fuch's disease, Glaucoma, immune complex vasculitis, inflammatory conjunctivitis, ischemic retinal disease, keratitis, macular edema, ocular parasitic infestation/migration, retinitis pigmentosa, scleritis, Stargardt disease, subretinal fibrosis, uveitis, vitreo-retinal inflammation, and Vogt- Koyanagi-Harada disease.
  • ATD Age-related macular degeneration
  • Ocular indications may include age-related macular degeneration (AMD).
  • AMD is a chronic ocular disease causing blurred central vision, blind spots in central vision, and/or eventual loss of central vision. Central vision affects ability to read, drive a vehicle and/or recognize faces.
  • AMD is generally divided into two types, non-exudative (dry) and exudative (wet). Dry AMD refers to the deterioration of the macula which is the tissue in the center of the retina.
  • Wet AMD refers to the failure of blood vessels under the retina leading to leaking of blood and fluid.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of AMD by inhibiting ocular complement activation.
  • Methods of the present disclosure involving the use of complement inhibitor compounds and compositions for prevention and/or treatment of AMD may include any of those taught in US publication Nos. US2011/0269807 or US2008/0269318, the contents of each of which are herein incorporated by reference in their entirety.
  • Ocular indications may include corneal disease.
  • the complement system plays an important role in protection of the cornea from pathogenic particles and/or inflammatory antigens.
  • the cornea is the outermost front part of the eye covering and protecting the iris, pupil and anterior chamber and is therefore exposed to external factors.
  • Corneal diseases include, but are not limited to, keratoconus, keratitis, ocular herpes and/or other diseases. Corneal complications may cause pain, blurred vision, tearing, redness, light sensitivity and/or corneal scarring.
  • the complement system is critical for corneal protection, but complement activation may cause damage to the corneal tissue after an infection is cleared as certain complement compounds are heavily expressed.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of corneal diseases by inhibiting ocular complement activation.
  • Methods of the present disclosure for modulating complement activity in the treatment of corneal disease may include any of those taught by Jha et al. in Mol Immunol. 2007; 44(16): 3901–8, the contents of which are herein incorporated by reference in their entirety.
  • Ocular indications may include autoimmune uveitis.
  • Uvea is the pigmented area of the eye including the choroids, iris and ciliary body of the eye. Uveitis causes redness, blurred vision, pain, synechia and may eventually cause blindness. Studies have indicated that complement activation products are present in the eyes of patients with autoimmune uveitis and complement plays an important role in disease development. In some
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of uveitis. Such treatments may be carried out according to any of the methods identified in Jha et al. in Mol Immunol.2007. 44(16): 3901–8, the contents of which are herein incorporated by reference in their entirety. Diabetic retinopathy
  • Ocular indications may include diabetic retinopathy, which is a disease caused by changes in retinal blood vessels in diabetic patients. Retinopathy may cause blood vessel swelling and fluid leaking and/or growth of abnormal blood vessels. Diabetic retinopathy affects vision and may eventually lead to blindness. Studies have suggested that activation of complement has an important role in the development of diabetic retinopathy.
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of diabetic retinopathy.
  • Complement inhibitor compounds and compositions may be used according to methods of diabetic retinopathy treatment described in Jha et al. Mol Immunol.2007; 44(16): 3901–8, the contents of which are herein incorporated by reference in their entirety. Stargardt’s disease
  • Ocular indications may include Stargardt’s disease.
  • Stargardt’s disease also called recessive Stargardt’s macular degeneration is an inherited disease of the eye, with an age of onset within the first two decades of life.
  • Complications from Stargardt’s disease may include loss of vision (Radu et al.,J. Biol. Chem, 2011286(21) 18593-18601).
  • the disease results from a mutation in the ABCA4 gene.
  • the hallmark of the disease includes
  • complement inhibitor compounds and compositions of the present disclosure may be used to treat, prevent, or delay development of Stargardt’s disease, e.g., by inhibiting ocular complement activation.
  • Therapeutic indications addressed with compounds and/or compositions of the present disclosure may include pregnancy-related indications.
  • pregnancy-related indications refers to any therapeutic indication involving child birth and/or pregnancy.
  • Pregnancy-related indications may include complement-related indications.
  • Pregnancy-related indications may include pre-eclampsia and/or HELLP
  • Pre-eclampsia is a disorder of pregnancy with symptoms including elevated blood pressure, swelling, shortness of breath, kidney dysfunction, impaired liver function and/or low blood platelet count.
  • Pre-eclampsia is typically diagnosed by a high urine protein level and high blood pressure.
  • HELLP syndrome is a combination of hemolysis, elevated liver enzymes and low platelet conditions.
  • Hemolysis is a disease involving rupturing of red blood cells leading to the release of hemoglobin from red blood cells. Elevated liver enzymes may indicate a pregnancy-induced liver condition. Low platelet levels lead to reduced clotting capability, causing danger of excessive bleeding.
  • HELLP is associated with a pre-eclampsia and liver disorder.
  • HELLP syndrome typically occurs during the later stages of pregnancy or after childbirth. It is typically diagnosed by blood tests indicating the presence of the three conditions it involves. Typically HELLP is treated by inducing delivery.
  • Complement inhibitors of the present disclosure may be used as therapeutic agents to prevent and/or treat these and other pregnancy-related indications.
  • Complement inhibitor compounds and compositions may be used according to methods of preventing and/or treating HELLP and pre-eclampsia taught by Heager et al. in Obstetrics & Gynecology, 1992, 79(1):19-26 or in International publication No. WO2014/078622, the contents of each of which are herein incorporated by reference in their entirety.
  • compounds and/or compositions of the present disclosure may be provided using any dosage and/or route of administration that yields a therapeutically effective result.
  • C5 inhibitors are administered at a milligram dosage.
  • Such doses may include from about 0.01 mg to about 1 mg, from about 0.05 mg to about 2 mg, from about 0.1 mg to about 10 mg, from about 0.5 mg to about 20 mg, from about 1 mg to about 30 mg, from about 5 mg to about 50 mg, from about 10 mg to about 75 mg, from about 50 mg to about 100, from about 100 mg to about 500 mg, from about 200 mg to about 750 mg, from about 500 mg to about 1000 mg, or at least 1000 mg.
  • subjects may be administered a therapeutic amount of a C5 inhibitor compound based on the weight of such subjects.
  • compounds are administered at a dose of from about 0.001 mg/kg to about 1.0 mg/kg, from about 0.01 mg/kg to about 2.0 mg/kg, from about 0.05 mg/kg to about 5.0 mg/kg, from about 0.03 mg/kg to about 3.0 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 2.0 mg/kg, from about 0.2 mg/kg to about 3.0 mg/kg, from about 0.4 mg/kg to about 4.0 mg/kg, from about 1.0 mg/kg to about 5.0 mg/kg, from about 2.0 mg/kg to about 4.0 mg/kg, from about 1.5 mg/kg to about 7.5 mg/kg, from about 5.0 mg/kg to about 15 mg/kg, from about 7.5 mg/kg to about 12.5 mg/kg, from about 10 mg/kg to about 20 mg/kg, from about 15 mg/kg to
  • Such ranges may include ranges suitable for administration to human subjects. Dosage levels may be highly dependent on the nature of the condition; drug efficacy; the condition of the patient; the judgment of the practitioner; and the frequency and mode of administration. [0306] In some cases, compounds of the present disclosure are provided at concentrations adjusted to achieve a desired level of the C5 inhibitor in a sample, biological system, or subject (e.g., plasma level in a subject).
  • concentrations adjusted to achieve a desired level of the C5 inhibitor in a sample, biological system, or subject e.g., plasma level in a subject.
  • sample refers to an aliquot or portion taken from a source and/or provided for analysis or processing.
  • a sample is from a biological source such as a tissue, cell or component part (e.g.
  • a body fluid including but not limited to blood, mucus, lymphatic fluid, synovial fluid, cerebrospinal fluid, saliva, amniotic fluid, amniotic cord blood, urine, vaginal fluid and semen).
  • a sample may be or comprise a homogenate, lysate or extract prepared from a whole organism or a subset of its tissues, cells or component parts, or a fraction or portion thereof, including but not limited to, for example, plasma, serum, spinal fluid, lymph fluid, the external sections of the skin, respiratory, intestinal, and genitourinary tracts, tears, saliva, milk, blood cells, tumors, organs.
  • a sample is or comprises a medium, such as a nutrient broth or gel, which may contain cellular components, such as proteins or nucleic acid molecule.
  • a“primary” sample is an aliquot of the source.
  • a primary sample is subjected to one or more processing (e.g., separation, purification, etc.) steps to prepare a sample for analysis or other use.
  • processing e.g., separation, purification, etc.
  • the term“subject” refers to any organism to which a compound in accordance with the present disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, porcine subjects, non-human primates, and humans.)
  • desired concentrations of compounds in a sample, biological system, or subject may include concentrations of from about 0.001 mM to about 0.01 mM, from about 0.005 mM to about 0.05 mM, from about 0.02 mM to about 0.2 mM, from about 0.03 mM to about 0.3 mM, from about 0.05 mM to about 0.5 mM, from about 0.01 mM to about 2.0 mM, from about 0.1 mM to about 50 mM, from about 0.1 mM to about 10 mM, from about 0.1 mM to about 5 mM, or from about 0.2 mM to about 20 mM.
  • desired concentrations compounds in subject plasma may be from about 0.1 mg/mL to about 1000 mg/mL. In other cases, desired concentrations of compounds in subject plasma may be from about 0.01 mg/mL to about 2 mg/mL, from about 0.02 mg/mL to about 4 mg/mL, from about 0.05 mg/mL to about 5 mg/mL, from about 0.1 mg/mL to about 1.0 mg/mL, from about 0.2 mg/mL to about 2.0 mg/mL, from about 0.5 mg/mL to about 5 mg/mL, from about 1 mg/mL to about 5 mg/mL, from about 2 mg/mL to about 10 mg/mL, from about 3 mg/mL to about 9 mg/mL, from about 5 mg/mL to about 20 mg/mL, from about 10 mg/mL to about 40 mg/mL, from about 30 mg/mL to about 60 mg/mL, from about 40 mg/mL to about 80 mg/mL, from about 50 mg/mL to about 100
  • compounds are administered at a dose sufficient to achieve a maximum serum concentration (C max ) of at least 0.1 mg/mL, at least 0.5 mg/mL, at least 1 mg/mL, at least 5 mg/mL, at least 10 mg/mL, at least 50 mg/mL, at least 100 mg/mL, or at least 1000 mg/mL.
  • C max maximum serum concentration
  • doses sufficient to sustain compound levels of from about 0.1 mg/mL to about 20 mg/mL are provided to reduce hemolysis in a subject by from about 25% to about 99%.
  • compounds are administered daily at a dose sufficient to deliver from about 0.1 mg/day to about 60 mg/day per kg weight of a subject.
  • the Cmax achieved with each dose is from about 0.1 mg/mL to about 1000 mg/mL.
  • the area under the curve (AUC) between doses may be from about 200 mg*hr/mL to about 10,000 mg*hr/mL.
  • C5 inhibitor compounds and compositions are provided at concentrations needed to achieve a desired effect.
  • C5 inhibitor compounds and compositions are provided at an amount necessary to reduce a given reaction or process by half. The concentration needed to achieve such a reduction is referred to herein as the half maximal inhibitory concentration, or“IC50.”
  • C5 inhibitor compounds and compositions may be provided at an amount necessary to increase a given reaction, activity or process by half. The concentration needed for such an increase is referred to herein as the half maximal effective concentration of “EC 50 .”
  • the C5 inhibitors of the present disclosure may be present in amounts totaling 0.1- 95% by weight of the total weight of the composition.
  • the C5 inhibitor compounds may be administered by any route which results in a therapeutically effective outcome.
  • the administration routes may include, but are not limited to enteral, gastroenteral, epidural, oral, transdermal, peridural, intracerebral,
  • intracerebroventricular epicutaneous, intradermal, subcutaneous, nasal administration, intravenous, intraarterial, intramuscular, intracardiac, intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraperitoneal, (into the peritoneum), intravesical infusion, intravitreal, (through the eye), intracavernous injection (into a pathologic cavity), intracavitary (into the base of the penis), intravaginal administration, intrauterine, extra-amniotic administration, transdermal, transmucosal, transvaginal, insufflation (snorting), sublingual, sublabial, enema, eye drops (onto the conjunctiva), in ear drops, auricular (in or by way of the ear), buccal (directed toward the cheek), conjunctival, cutaneous, dental (to a tooth or teeth), electro-osmosis, endocervical, endosinusial,
  • intragingival within the gingivae
  • intraileal within the distal portion of the small intestine
  • intralesional within or introduced directly to a localized lesion
  • intraluminal within a lumen of a tube
  • intralymphatic within the lymph
  • intramedullary within the marrow cavity of a bone
  • intrameningeal within the meninges
  • intraocular within the eye
  • intraovarian within the ovary
  • intrapericardial within the pericardium
  • intrapleural within the pleura
  • intraprostatic within the prostate gland
  • intrapulmonary within the lungs or its bronchi
  • intrasinal within the nasal or periorbital sinuses
  • intraspinal within the vertebral column
  • intrasynovial within the synovial cavity of a joint
  • intratendinous within a tendon
  • intratesticular within the testicle
  • intrathecal within the cerebrospin
  • C5 inhibitor compounds may be formulated to be suitable for oral delivery.
  • the compounds may be administered in any suitable form, either as a liquid solution, or as a solid form, such as a tablet, pill, capsule, or a powder.
  • Small molecule compounds have the advantage of being suitable for oral delivery, whereas biomolecules generally require other methods, e.g., injection delivery.
  • Oral administration of the C5 inhibitor compounds and compositions may, in some cases, provide advantages over other delivery routes. Such treatment may be advantageous in that patients could provide treatment to themselves in their own home, avoiding the need to travel to a provider or medical facility.
  • Oral administration may avoid complications and risks associated with administration that requires needles, such as infections, loss of venous access, local thrombosis, and hematomas.
  • Oral deliverables may be formulated to be slowly releasing, allowing the medication to be effective over an extended period of time.
  • the C5 inhibitor compounds and compositions are provided by subcutaneous administration.
  • the C5 inhibitor compounds and compositions are provided by intravenous (IV) administration.
  • the C5 inhibitor compounds and compositions are provided by ocular delivery routes including, but not limited to, intraocular, ophthalmic, retrobulbar, intravitreal and/or drops on to the conjunctiva.
  • ocular delivery routes including, but not limited to, intraocular, ophthalmic, retrobulbar, intravitreal and/or drops on to the conjunctiva.
  • Such methods may include administration of liquid solution eye drops, eye emulsions, suspensions and ointments, ocular injections, or administration by ocular implant release.
  • the C5 inhibitor compounds and compositions are provided by topical delivery methods.
  • Such methods may include administration of a topical solution, e.g. a lotion, cream, ointment, emulsion, gel, foam, or a transdermal patch.
  • dosage and/or administration are altered to modulate the half-life (t 1/2 ) of C5 inhibitor compound levels in a subject or in subject fluids (e.g., plasma).
  • t1/2 is at least 1 hour, at least 2 hrs, at least 4 hrs, at least 6 hrs, at least 8 hrs, at least 10 hrs, at least 12 hrs, at least 16 hrs, at least 20 hrs, at least 24 hrs, at least 36 hrs, at least 48 hrs, at least 60 hrs, at least 72 hrs, at least 96 hrs, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, or at least 16 weeks.
  • C5 inhibitor compounds of the present disclosure may exhibit long terminal t1/2. Extended terminal t1/2 may be due to extensive target binding and/or additional plasma protein binding. In some cases, C5 inhibitor compounds of the present disclosure exhibit t 1/2 values greater than 24 hours in both plasma and whole blood. In some cases, compounds do not lose functional activity after incubation in human whole blood at 37°C for 16 hours.
  • dosage and/or administration are altered to modulate the steady state volume of distribution of C5 inhibitor compounds.
  • the steady state volume of distribution of compounds is from about 0.1 mL/kg to about 1 mL/kg, from about 0.5 mL/kg to about 5 mL/kg, from about 1 mL/kg to about 10 mL/kg, from about 5 mL/kg to about 20 mL/kg, from about 15 mL/kg to about 30 mL/kg, from about 10 mL/kg to about 200 mL/kg, from about 20 mL/kg to about 60 mL/kg, from about 30 mL/kg to about 70 mL/kg, from about 50 mL/kg to about 200 mL/kg, from about 100 mL/kg to about 500 mL/kg, or at least 500 mL/kg.
  • the dosage and/or administration of compounds is adjusted to ensure that the steady state volume of distribution is equal to at least 50%
  • C5 inhibitor compounds of the present disclosure exhibit a total clearance rate of from about 0.001 mL/hr/kg to about 0.01 mL/hr/kg, from about 0.005 mL/hr/kg to about 0.05 mL/hr/kg, from about 0.01 mL/hr/kg to about 0.1 mL/hr/kg, from about 0.05 mL/hr/kg to about 0.5 mL/hr/kg, from about 0.1 mL/hr/kg to about 1 mL/hr/kg, from about 0.5 mL/hr/kg to about 5 mL/hr/kg, from about 0.04 mL/hr/kg to about 4 mL/hr/kg, from about 1 mL/hr/kg to about 10 mL/hr/kg, from about 5 mL/hr/kg to about 20 mL/hr/kg, from about 15 mL/hr/kg
  • Time periods for which maximum concentration of C5 inhibitor compounds in subjects (e.g., in subject serum) are maintained may be adjusted by altering dosage and/or administration (e.g., subcutaneous administration).
  • C5 inhibitors have Tmax values of from about 1 min to about 10 min, from about 5 min to about 20 min, from about 15 min to about 45 min, from about 30 min to about 60 min, from about 45 min to about 90 min, from about 1 hour to about 48 hrs, from about 2 hrs to about 10 hrs, from about 5 hrs to about 20 hrs, from about 10 hrs to about 60 hrs, from about 1 day to about 4 days, from about 2 days to about 10 days, or at least 10 days.
  • “lower” or“reduce” in the context of a disease marker or symptom is meant a statistically significant decrease in such level.
  • the decrease may be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and is preferably down to a level accepted as within the range of normal for an individual without such disorder.
  • By“increase” or“raise” in the context of a disease marker or symptom is meant a statistically significant rise in such level.
  • the increase may be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and is preferably up to a level accepted as within the range of normal for an individual without such disorder.
  • prophylactically effective amount refers to an amount that provides a therapeutic benefit in the treatment, prevention, or management of pathological processes or an overt symptom of one or more pathological processes.
  • the specific amount that is therapeutically effective may be readily determined by an ordinary medical practitioner, and may vary depending on factors known in the art, such as, for example, the type of pathological processes, patient history and age, the stage of pathological processes, and the administration of other agents that inhibit pathological processes.
  • compositions of the present disclosure may include a
  • pharmacologically effective amount of a C5 inhibitor compound and a pharmaceutically acceptable carrier.
  • “pharmacologically effective amount,”“therapeutically effective amount” or simply“effective amount” refers to that amount of a compound effective to produce the intended pharmacological, therapeutic or preventive result. For example, if a given clinical treatment is considered effective when there is at least a 10% alteration (increase or decrease) in a measurable parameter associated with a disease or disorder, a therapeutically effective amount of a drug for the treatment of that disease or disorder is the amount necessary to effect at least a 10% alteration in that parameter.
  • a therapeutically effective amount of a compound may be one that alters binding of a target to its natural binding partner by at least 10%.
  • pharmaceutically acceptable carrier refers to a carrier for
  • Such carriers include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.
  • pharmaceutically acceptable carriers include, but are not limited to pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives.
  • suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Agents included in drug formulations are described further herein below.
  • Efficacy of treatment or amelioration of disease may be assessed, for example by measuring disease progression, disease remission, symptom severity, reduction in pain, quality of life, dose of a medication required to sustain a treatment effect, level of a disease marker or any other measurable parameter appropriate for a given disease being treated or targeted for prevention. It is well within the ability of one skilled in the art to monitor efficacy of treatment or prevention by measuring any one of such parameters, or any combination of parameters.
  • a disease or disorder in connection with the administration of a small molecule compound or pharmaceutical composition thereof, "effective against" a disease or disorder indicates that administration in a clinically appropriate manner results in a beneficial effect for at least a fraction of patients, such as an improvement of symptoms, a cure, a reduction in disease load, reduction in tumor mass or cell numbers, extension of life, improvement in quality of life, a reduction in the need for blood transfusions or other effect generally recognized as positive by medical doctors familiar with treating the particular type of disease or disorder.
  • a treatment or preventive effect is evident when there is a statistically significant improvement in one or more parameters of disease status, or by a failure to worsen or to develop symptoms where they would otherwise be anticipated.
  • a favorable change of at least 10% in a measurable parameter of disease, and preferably at least 20%, 30%, 40%, 50% or more may be indicative of effective treatment.
  • Efficacy for a given drug or formulation of that drug may also be judged using an experimental animal model for the given disease as known in the art. When using an experimental animal model, efficacy of treatment is evidenced when a statistically significant modulation in a marker or symptom is observed.
  • C5 inhibitor compounds and additional therapeutic agents may be administered in combination in the same composition, e.g., parenterally, or may be administered as part of separate compositions or by other methods described herein.
  • C5 inhibitors of the present disclosure may be modified and/or formulated for various forms of administration.
  • the C5 inhibitors may be modified and/or formulated as active metabolites.
  • active metabolite refers to a form of a compound resulting when a compound is metabolized by the body.
  • the active metabolite of a compound may have the same, reduced, or enhanced therapeutic effect when compared to the unmetabolized form. In some cases, the active metabolite may cause fewer or no side-effects compared with the unmetabolized form.
  • C5 inhibitors of the present disclosure may be modified and/or formulated to enhance absorption, distribution, metabolism and/or excretion.
  • modifications may include preparation as a prodrug.
  • prodrug refers to an inactive compound that may be metabolized to generate an active form. Such active forms may be pharmacologically active.
  • C5 inhibitor prodrugs may vary in one or more of absorption, distribution, metabolism and/or excretion as compared to an unmodified C5 inhibitor.
  • C5 inhibitor prodrugs may have improved bioavailability.
  • C5 inhibitor prodrugs, including, but not limited to, C5 inhibitor prodrugs with improved bioavailability may have enhanced properties suitable for oral administration when compared to unmodified C5 inhibitors.
  • compounds of the present disclosure may be used in in vitro and in vivo ADME (Absorption, Distribution. Metabolism, Excretion) assays to determine their pharmacological properties of absorption, distribution, metabolism, and excretion.
  • ADME assays include, but are not limited to, plasma protein binding assays, plasma stability assays, hepatocyte stability assays, microsomal binding and stability assays, and permeability assays.
  • In vivo evaluation of ADME characteristics may be carried out by, but not limited to, metabolite profiling, bioavailability and tissue distribution techniques. Characterization of ADME properties of the compounds described in the present disclosure may be used to determine/improve dosage and administration methods.
  • C5 inhibitors may include one or more modifications of a phenyl glycinol functional site to form a prodrug. Such modifications may include the addition of an ester group or a phosphate group.
  • Formulas IIa and IIb present prodrug structures based on compound SM0011 with an ester group and a phosphate group, respectively.
  • aliphatic refers to a straight or branched C 1 -C8 hydrocarbon chain or a monocyclic C3-C8 hydrocarbon or bicyclic C8- C12 hydrocarbon which is fully saturated or that contains one or more units of unsaturation, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” or “cycloalkyl”), and that has a single point of attachment to the rest of the molecule wherein any individual ring in the bicyclic ring system has 3-7 members.
  • Suitable aliphatic groups include, but are not limited to, linear or branched alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • alkyl include both straight and branched chains containing one to twelve carbon atoms, and/or which may or may not be substituted.
  • alkenyl and alkynyl as used herein alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve carbon atoms.
  • aromatic refers to an unsaturated hydrocarbon ring structure with delocalized pi electrons.
  • aromatic may refer to monocyclic, bicyclic, or polycyclic aromatic compounds.
  • aryl as used herein alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of five to fourteen ring members, wherein at least one ring is aromatic and wherein each ring in the system contains 3 to 8 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • the term“bond” as used herein, refers to any chemically feasible bonding configuration that connects immediately adjacent atoms and/or functional groups.
  • the term“functional group” as used herein, refers to a specific portion of a molecule that is responsible for certain characteristic chemical properties of the molecule. A molecule may have one or more functional groups.
  • haloalkyl refers to alkyl, alkenyl or alkoxy, optionally substituted with one or more halogen atoms.
  • halogen refers to F, CI, Br, or I.
  • heteroatom refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
  • heterocycle refers to monocyclic, bicyclic or tricyclic ring systems having three to fourteen ring members in which one or more ring members is a heteroatom, wherein each ring in the system contains 3 to 7 ring members and is non-aromatic.
  • heteroaryl as used herein alone or as part of a larger moiety as in “heteroaralkyl” or “heteroalkylalkoxy”, refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, and wherein: 1) at least one ring in the system is aromatic; 2) at least one ring in the system contains one or more heteroatoms; and 3) each ring in the system contains 3 to 7 ring members.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic.”
  • An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl, heteroalkylalkoxy and the like) group can contain one or more substituents.
  • Substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group can be selected from the group including, but not limited to: halogen; haloalkyl; -CF 3 ; -R ⁇ ; -OR ⁇ ; -SR ⁇ ; 1,2- methylene-dioxy; 1,2-ethylenedioxy; dimethyleneoxy; protected OH (such as acyloxy); phenyl (Ph); Ph substituted with R ⁇ ; -O(Ph); -O-(Ph) substituted with R ⁇ ; -CH 2 (Ph); -CH 2 (Ph) substituted with R ⁇ ; -CH 2 CH 2 (Ph); -CH 2 CH 2 (Ph) substituted with R ⁇ ; -NO 2 ; -CN; -N(R ⁇ ) 2 ; -NR ⁇ C(O)R ⁇ ; -NR ⁇ C
  • R ⁇ is C 1 -6 aliphatic, it is optionally substituted with one or more substituents selected from -NH 2 , -NH(C 1 -4 aliphatic), -N(C 1 -4 aliphatic) 2 , -S(O) (C 1 - 4 aliphatic- aliphatic), -SO 2 (C 1 - 4 aliphatic), halogen, -(C 1-4 aliphatic), -OH, -O-( C 1-4 aliphatic), -NO 2 , -CN, -CO 2 H, -CO 2 (C 1-4 aliphatic), -O(halo C 1-4 aliphatic), or -halo(C 1- 4 aliphatic); wherein each C 1 -4 aliphatic is unsubstituted.
  • An aliphatic group or a non-aromatic heterocyclic ring as described above may contain one or more substituents.
  • R * is C C 1 -6 aliphatic, it is optionally substituted with one or more substituents selected from -NH 2 , -NH(C C 1-4 aliphatic), -N(C 1-4 aliphatic) 2 , halogen, -OH, -O-(C 1-4 aliphatic), -NO 2 , -CN, - CO 2 H, -CO 2 (C C 1 -4 aliphatic), -O(halo C 1 -4 aliphatic), or -halo(C 1 -4 aliphatic); wherein each C 1 -4 aliphatic is unsubstituted.
  • each R is independently selected from hydrogen, an optionally substituted C 1 - 6 aliphatic, optionally substituted phenyl (Ph), optionally substituted -O(Ph), optionally substituted -CH 2 (Ph), optionally substituted - CH 2 CH 2 (Ph), or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring.
  • R + is a C 1-6 aliphatic group or a phenyl ring, it is optionally substituted with one or more substituents selected from -NH 2 , -NH(C 1-4 aliphatic), -N(C 1-4 aliphatic) 2 , halogen, -(C 1- 4 aliphatic), -OH, -O-(C aliphatic), -NO 2 , -CN, -CO 2 H, -CO 2 (C 1 -4aliphatic), -O(halo C 1 - 4 aliphatic), or -halo(C 1 -4 aliphatic); wherein each C 1 -6 aliphatic is unsubstituted.
  • linker group refers to an organic moiety that connects two parts of a compound.
  • Linkers are comprised of - O-, -S-, -NR*-, -C(R*) 2 -, - C(O)-, or an alkylidene chain.
  • the alkylidene chain is a saturated or unsaturated, straight or branched, C 1-6 carbon chain which is optionally substituted, and wherein up to two non- adjacent saturated carbons of the chain are optionally replaced by -C(O)-, -C(O)C(O)-, - C(O)NR*-, -C(O)NR*NR*-, -CO 2 -, -OC(O)-, -NR*CO 2 -, -O-, -NR*C(O)NR*-, - OC(O)NR*-, -NR*NR*-, -NR*C(O)-, -S-, -SO-, -SO 2 -, -NR*-, -SO 2 NR*-, or -NR*SO 2 -; wherein R* is selected from hydrogen or C 1-4 aliphatic.
  • nitrogen may be N, NH or NR + .
  • the nitrogen may be N (as in 3,4- dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).
  • saturated refers to a hydrocarbon which has single bonds between the carbon atoms and may contain other atoms.
  • substitution refers to the replacement of a functional group of a chemical compound by another functional group.
  • substituted refers to an atom or functional group other than hydrogen, that replaces a hydrogen atom on a hydrocarbon.
  • substituents include atoms (e.g., halogens, heteroatoms) and functional groups (e.g.
  • aliphatic groups, aryl groups, and heteroaryl groups -OH, oxo, -O-(C 1 -C 4 )-alkyl, halogen, -CF 3 , nitrile, -COOH, -CO-NH 2 , -O-CO-NH 2 , -OCF 3 , -N(H) (C 1 -C 4 -alkyl), and -N-(C 1 -C 4 -alkyl) 2 ).
  • the term“unsaturated” as used herein, refers to a hydrocarbon which has double or triple bonds between the carbon atoms and may contain other atoms.
  • the term“partially unsaturated” as used herein, refers to hydrocarbon that has at least one double or triple bond between the carbon atoms and may contain other atoms.
  • articles such as“a,”“an,” and“the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include“or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the invention includes embodiments in which more than one, or the entire group members are present in, employed in, or otherwise relevant to a given product or process.
  • any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the invention (e.g., any therapeutic or active ingredient; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.
  • Analytical LCMS was performed by Waters Acquity SDS using a linear gradient of 5% to 100 % B over a 5 minute gradient, and UV visualization with a diode array detector.
  • the column used was a C18 Acquity UPLC BEH, 2.1 mm i.d. by 50 mm length, 1.7 mM with flow rate of 0.6 ml/min.
  • Mobile phase A was water and mobile phase B was acetonitrile (0.1% TFA). Results are shown in Table 4.
  • the sensor chip was activated by using a mixture of fresh EDAC (1-ethyl-3-(-3- dimethylaminopropyl) carbodiimide) (Sigma Co., St. Louis, MO) and NHS (N-hydroxy succinimide) (Sigma Co., St. Louis, MO).
  • Human C5 was surface immobilized to a Pioneer Biosensor chip via random amine coupling (>12,000RU) which makes use of the N-terminus and e-amino groups of lysine residues of the protein ligand. Immobilization was done by injecting 30-40 mg/ml C5 in 10mM NaAc pH 4.5 onto designated channels at a rate of 10 mL /minute for 12 minutes, targeting RL >12000RU for small molecules.
  • RBC red blood cell
  • GVB++ buffer Complement Technology, Tyler, TX
  • the human C5 depleted sera and purified human C5 were rapidly thawed at 37°C and then stored on ice or wet ice, respectively.
  • the compound stock (10mM, DMSO) was serially diluted in 100% DMSO to obtain ten 6-fold dilutions before addition of GVB++.
  • Sera dilution was prepared by adding 5 mL of GVB++ to a 15 mL conical tube, removing 600 mL of the GVB++ and adding 600 mL of the 100% sera. The tube was mixed by inverting three times.
  • C5 dilution was prepared by adding 5 mL of GVB++ to a 15 mL conical tube, removing 4 mL of the GVB++ and adding 4 mL of the C5 stock. The tube was mixed by inverting three times. A volume of 25 mL was added to each well so that the final amount of C5 was 0.5 nM in each well.
  • the antibody-sensitized sheep erythrocytes (EAs) were centrifuged at 1,000 x gravity at 22°C for 3 minutes. The supernatant was pipetted off without disrupting the pellet. The pellet was then resuspended in GVB++ with the same volume removed. Resuspended EAs were mixed by gently inverting the tube.
  • EAs only 100 mL EAs + 50 mL GVB++ with 4% DMSO + 50 mL GVB++;
  • EA + Sera 100 mL EAs + 50 mL GVB++ with 4% DMSO + 25 mL Sera dilution + 25 mL GVB++;
  • EA + C5 100 mL EAs + 50 mL GVB++ with 4% DMSO + 25 mL C5 dilution + 25 mL GVB++;
  • EA + Sera + C5 100 mL EAs + 50 mL GVB++ with 4% DMSO + 25 mL Sera dilution + 25 mL C5;
  • GVB++ Only 200 mL GVB++.
  • GVB++ with 4% DMSO 20 mL DMSO + 480 mL GVB++. All samples were analyzed in duplicate. The compound dose response curve was generated using samples prepared with 100 mL EA + 50 mL compound dilution + 25 mL C5 dilution + 25 mL sera dilution.
  • Test plates were prepared by adding 100 mL of EAs, 50 mL of compound dilution, 25 mL of sera dilution, and 25 mL of C5 dilution to individual wells of a 96-well tissue culture-treated clear microtitre plate (USA Scientific, Ocala, FL) and resuspending by pipetting up and down three times. The samples were incubated at 37°C for one hour. At the completion of the incubation, the plates were centrifuged at 1,000 x gravity for 3 minutes. 100 ml of supernatant were transferred to a new plate and the absorbance was read at 412 nm. Data was fit with a log-logit formula producing a dose-response curve and IC50.
  • IC 50 refers to the half maximal inhibitory concentration, where the value is the concentration of the inhibitor needed to reduce red blood cell hemolysis by half. Where replicate analysis was conducted, average IC 50 values are provided along with standard deviation (SD) values.
  • EA cells Sheep red blood cells coated with rabbit anti-sheep erythrocyte antiserum (EA cells; Complement Technology, Tyler, Texas) were used to assay compound inhibitory activity of the classical complement activation pathway. Briefly, the EA cells were washed once and resuspended in the same volume of GVB++ buffer (Complement Technology, Tyler, TX).25mL of EA cells were then distributed into each well of 384-well tissue culture plates using Apricot iPipette Pro (Apricot Designs; Covina, CA). Compounds were tested in 10 points of final concentrations ranging from 16.67 mM to 1.65 pM in a 6-fold titration series.
  • Luminescence measurements were used to prepare a dose-response curve. From the curve, the half maximal inhibitory concentration (IC 50 ) for each compound was determined, where the IC50 represents the concentration of each compound needed to reduce red blood cell hemolysis by half. Results are presented in Table 7. Numbers in parenthesis following the compound number indicate alternate enantiomers (as distinguished by retention time during chromatographical separation).
  • SM0011 was formulated as a clear solution at 1 mg/mL in 5% DMSO: 20% HP- Beta-CD. Fasted male Sprague Dawley rats were dosed with the solution at 1 MPK (mg/kg) IV and 10 MPK (mg/kg) PO. Analysis of the DMPK properties of the compound were used to determine the bioavailability. Results indicated that the bioavailability of SM0011 was about 30%.
  • FACS fluorescence-associated cell sorting
  • the level of CD59-positive cells was monitored as a measure of complement- mediated hemolysis of PNH type III cells.
  • a negative control using non-acidified serum was used to establish a baseline of CD59 expression under non-hemolytic conditions (Fig.1A).
  • acidified serum was introduced, the level of CD59 expression decreased, consistent with RBC hemolysis (Fig.1B).
  • Hemolysis was blocked in the presence of eculizumab, which is a known antibody-based C5 inhibitor (Fig.1C). Similar inhibition was also observed with SM0001 (Fig.1D), demonstrating the ability of this compound to inhibit hemolysis in human PNH patient cells and the potential for using this compound as a substitute for eculizumab.
  • Step 1 Tert-butoxycarbonyl tert-butyl carbonate (79.6 g, 364 mmol, 84 mL, 1.00 eq) is added to a cooled (0 °C) solution of (2R)-2-amino-2-phenyl-ethanol (50.0 g, 364 mmol, 1.00 eq) and triethylamine (44.3 g, 437 mmol, 61 mL, 1.20 eq) in dry tetrahydrofuran (1.40 L). The mixture is stirred at 0 °C for 3 hours then concentrated in vacuo.
  • Step 2 A solution of tert-butyl N-[(1R)-2-hydroxy-1-phenyl-ethyl]carbamate (63.0 g, 265 mmol, 1.00 eq) and triethylamine (53.7 g, 531 mmol, 73 mL, 2.00 eq) in dry dichloromethane (1.40 L) is stirred at 25 °C for 1 h. Then acetic anhydride Ac 2 O (67.8 g, 664 mmol, 62 mL, 2.50 eq) is added. The mixture is stirred at 25 °C for 2 h.
  • Step 3 To a solution of [(2R)-2-(tert-butoxycarbonylamino)-2-phenyl-ethyl] acetate (63.0 g, 226 mmol, 1.00 eq) in dry dichloromethane (500 mL) is added HCl/dioxane (4 M, 564 mL). The mixture is stirred at 25 °C for 2 hours. The reaction mixture is concentrated in vacuo. [(2R)-2-amino-2-phenyl-ethyl] acetate (40.0 g, 223 mmol, 99% yield) is obtained as white solid.
  • Oxidation of isovanilins To a solution of 4-Methoxy-3-(((4- methylpentyl)oxy)benzaldehyde (54.2 mmol, 12.7 g) in acetonitrile (250 mL) at 0 °C is added 30 % hydrogen peroxide solution (81.2 mmol, 2.5 mL), a solution of sodium phosphate monobasic hydrate (0.3 g) and sodium chlorite (75.8 mmol, 6.8 g) in water (20 mL). The resulting solution is warmed to room temperature and allowed to stir for an additional 24 hours.
  • Step 1 To a solution of tert-butyl N-(3-benzyloxy-4-methoxy-phenyl)carbamate (3.00 g, 9.11 mmol, 1.00 eq) in methanol (150 mL) is added wet Pd-C (10%, 0.3 g) under N2. The suspension is degassed under vacuum and purged with H2 several times. The mixture is stirred under H 2 (50 psi) at 25 °C for 12 h. The reaction mixture is filtered and concentrated under reduced pressure to afford tert-butyl N-(3-hydroxy-4-methoxy-phenyl)carbamate (2.50 g, crude) as dark oil.
  • Step 2 To a solution of tert-butyl N-(3-hydroxy-4-methoxy-phenyl)carbamate (2.40 g, 10.0 mmol, 1.00 eq) in dimethylformamide (15 mL) is added cesium carbonate (6.54 g, 20.1 mmol, 2.00 eq) and 1-bromo-4-methyl-pentane (1.82 g, 11.0 mmol, 1.56 mL, 1.10 eq) dropwise. The mixture is stirred at 25 °C for 1.5 h. The reaction mixture is poured into water (50 mL), and extracted with ethyl acetate.
  • Step 3 A solution of tert-butyl N-(3-isohexyloxy-4-methoxy-phenyl)carbamate (2.50 g, 7.73 mmol, 1.00 eq) in hydrogen chloride (4 M in ethyl acetate, 150 mL) is stirred at 25 °C for 2 h. The reaction mixture is concentrated under reduced pressure, then diluted with aqueous sodium hydrogen carbonate (200 mL) and extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3-isohexyloxy-4-methoxy-aniline (1.60 g, 7.16 mmol, 92.7% yield) as dark oil.
  • Step 1 To a solution of (2R)-2-amino-2-phenyl-ethanol (5.00 g, 36.5 mmol, 1.00 eq) and imidazole (3.72 g, 54.7 mmol, 1.50 eq) in dichloromethane (50 mL) is added TBSCl (6.59 g, 43.7 mmol, 5.36 mL, 1.20 eq). The mixture is stirred at 25 °C for 2 hours. The reaction mixture is diluted with water (20 mL) and extracted with dichloromethane. The combined organic layers are washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 2 To a solution of (1R)-2-[tert-butyl(dimethyl)silyl]oxy-1-phenyl- ethanamine (4.20 g, 16.7 mmol, 1.00 eq) and DIPEA (4.32 g, 33.4 mmol, 5.84 mL, 2.00 eq) in tetrahydrofuran (30 mL) is added phenyl chloroformate (3.14 g, 20.0 mmol, 2.51 mL, 1.20 eq) in tetrahydrofuran (20 mL) dropwise. The mixture is stirred at 0 °C for 2 hours. The reaction mixture is diluted with water (30 mL) and extracted with dichloromethane.
  • Step 1 To a solution of 5-benzyloxy-6-methoxy-phenyl-3-carboxylic acid and [(2R)-2-amino-2-phenyl-ethyl] acetate (1.2 eq, HCl) in toluene (200 mL) is added triethylamine (3.0 eq). The mixture is refluxed in a Dean-Stack apparatus for 2 hrs to remove water, and then cooled to 85 °C. DPPA (1.2 eq) is added drop-wise. The mixture is stirred at 85 °C for 2 hrs.
  • reaction mixture is concentrated under reduced pressure, then diluted with water (200 mL) and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford [(2R)-2-[(5-benzyloxy-6-methoxy-3-phenyl) carbamoylamino]-2- phenyl-ethyl] acetate.
  • Step 2 To a solution of [(2R)-2-[(5-benzyloxy-6-methoxy-3- phenyl)carbamoylamino]-2-phenyl-ethyl] acetate (1.00 g, 2.30 mmol, 1.00 eq) in methanol (20 mL) is added Pd/C (200 mg, 10 % purity) under nitrogen. The suspension is degassed under vacuum and purged with H2 several times. The mixture is stirred under H2 (50 psi) at 25 °C for 12 hrs.
  • reaction mixture Upon completion, the reaction mixture is diluted with 100mL DCM and washed with 5% w/v aqueous citric acid and the DCM layer is dried over anhydrous MgSO4 and concentrated.
  • the crude residue is triturated with ⁇ 10%EtOAc in hexanes ( ⁇ 40 mL), sonicated, filtered and washed with hexanes to give a white solid (1.968g, 87%).
  • Step 1 To a solution of dibenzylamine (10mmol, 1.9gms), (2-(2- benzyloxy)phenyl)boronic acid (10 mmol, 2.3g) in methanol (10 mL) is added 2,2- dihydroxyacetic acid (10mmol, 0.9gms). The resulting solution is allowed to stir at room temperature for 12 hours then concentrated. The mixture is quenched with water and extracted with ethyl acetate. The organics are washed with brine then dried over sodium sulfate, and filtered. The filtrate is concentrated under vacuum to give a crude oil.
  • Step 2 Propyl chloroformate (3.4 mmol, 0.4 g) is added to a solution of 2-(2- (benzyloxy)phenyl-2-(dibenzylamino) acetic acid (3.4 mmol, 1.5 g) in dichloromethane (10 mL) at 0C (ice bath temperature). Triethylamine (4.1 mmol, 0.4 g) is added and the resulting solution is allowed to warm to room temperature and stir for 30 minutes. The reaction is quenched with water and extracted with dichloromethane. The organics are washed with brine then dried over sodium sulfate, and filtered. The filtrate is concentrated under vacuum to give a crude oil. The crude oil is dissolved in methanol (10 mL) and cooled to 0C.
  • Step 3 Hydrogenated 2-(2-(benzyloxy)phenyl-2-dibenzylamino)ethan-1-ol (1.8 mmol, 0.84 g) over palladium on carbon (10% by wt.) in methanol at 1 atmosphere. After 1 hour, the reaction is evacuated and flushed with nitrogen, filtered over celite, and the filtrate concentrated under vacuum to give 2-(1-amino-2-hydroxyethyl)phenol (0.3gms) as a clear oil.
  • DPPA (3.18 g, 11.6 mmol, 2.51 mL, 1.20 eq) was added drop-wise. The mixture was stirred at 85 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure, then diluted with water (200 mL) and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic layers were washed with brine (100 mL ⁇ 2), dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 1 A mixture of (R)-2-methylpropane-2-sulfinamide (8.3 mmol, 1gm), 2- ((tert-butyldimethylsilyl)oxy)acetaldehyde (8.3 mmol, 1.4 g), and copper (II) sulfate (16.5 mmol, 2.6 g) in dichloromethane (10 mL) is stirred at room temperature for 24 hours. The mixture is filtered over magnesium sulfate and the filtrate concentrated to give an oil.
  • Phenylmethanamine (amine) is added to the isocyanate crude reaction. Purified on C18 Flash 5 - 95% MeCN.
  • (R)-2-amino-2-phenylacetamide used in synthesis of Compound SM0102, is synthesized by hydrogenation of benzyl (R)-(2-amino-2-oxo-1-phenylethyl)carbamate (0.7 mmol, 0.21gm) over palladium on carbon (10% by wt.) in methanol at 1 atmosphere H 2 (gas). After 1 hour, the reaction is evacuated and flushed with nitrogen, filtered over celite, and the filtrate concentrated under vacuum to give (R)-2-amino-2-phenylacetamide (0.1g) as a clear oil.
  • Isovanillin is alkylated to make 3-(3-chloropropoxy)-4-methoxybenzaldehyde, which is then oxidized to the carboxylic acid, 3-(3-chloropropoxy)-4-methoxybenzoic acid.
  • 3-(3-chloropropoxy)-4-methoxybenzoic acid is converted to the isocyanate and trapped with the amine, (R)-2-amino-2-phenylethan-1-ol, to make Compound SM0051.
  • Step 1 To a mixture of Intermediate A6 (phenyl (R)-(2-((tert- butyldimethylsilyl)oxy)-1-phenylethyl)carbamate) (327 mg, 880 mmol, 1.20 eq) and triethylamine (223 mg, 2.20 mmol, 305 mL, 3.00 eq) in dioxane (3 mL) is added 3- aminophenol (80.0 mg, 733 mmol, 1.00 eq). The mixture is stirred at 110 °C for 12 hours. The reaction mixture is concentrated under reduced pressure to remove the solvent. The residue is diluted with water (10 mL) and extracted with ethyl acetate (10 mL ⁇ 2).
  • Steps 2 and 3 To a mixture of 1-[(1R)-2-[tert-butyl(dimethyl)silyl]oxy-1-phenyl- ethyl]-3-(3-hydroxyphenyl)urea (200 mg, 517 mmol, 1.00 eq) and cesium carbonate (337 mg, 1.03 mmol, 2.00 eq) in dimethyl formamide (2 mL) is added 1-bromo-4-methyl-pentane (102 mg, 620 mmol, 87.6 mL, 1.20 eq). The mixture is stirred at 25 °C for 12 hours.
  • reaction mixture is diluted with water (20 mL) and extracted with ethyl acetate (10 mL ⁇ 2). The combined organic layers are washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step 1 To a mixture of 4-fluoro-3-hydroxybenzaldehyde (5.7 mmol, 0.8 g), potassium carbonate (8.6 mmol, 1.2 g), and 18-Crown-6 (1.4 g) in DMF (10 mL) is added 1- bromo-4-methylpentane (6.8 mmol, 1.1 g). The resulting mixture is stirred for 12 hours then quenched with water and extracted with ethyl acetate. The organics are washed with brine then dried over sodium sulfate, and filtered. The filtrate is concentrated under vacuum to give a crude oil.
  • Step 2 To a solution of 4-fluoro-3-(((4-methylpentyl)oxy)benzaldehyde (4.5 mmol, 1.0 g) in acetonitrile (10 mL) at 0 °C is added 30% hydrogen peroxide solution (6.7 mmol, 0.3 mL), a solution of sodium phosphate monobasic hydrate (0.02 g) and sodium chlorite (6.7 mmol, 0.60 g) in water (2 mL). The resulting solution is warmed to room temperature and allowed to stir for an addition 24 hours. The reaction is quenched with a saturated solution of sodium thiosulfate then extracted with ethyl acetate.
  • Step 3 A mixture of 4-fluoro-3-(((4-methylpentyl)oxy)benzoic acid (3.7 mmol, 0.9 g), diphenyl phosphoryl azide (4.5 mmol, 1.2 g), and triethylamine (5.3 mmol, 0.54 g) in toluene (20 mL) is heated at 70 °C for 12 hours. The mixture is cooled and concentrated under vacuum to give a 1-fluoro-4-siocyanato-2-((4-methylpenyl)oxy)benzene as a crude oil.
  • Step 4 To a solution of the isocyanate of Step 3 in DCM (1 mL) is added a solution of (R)-2-amino-2-phenylethan-1ol (an amine, 2-amino-2-(4-fluorophenyl)ethan-1-ol, (CAS# 140373-17-7) (1 eq) in DCM (1 mL). The reaction is stirred for 15 minutes, volatiles were removed in vacuo. The compound is purified on C18 reverse phase flash
  • Step 1 To a mixture of 6-nitro-1H-indazole (1.00 g, 6.13 mmol, 1.00 eq) in DMF (20 mL) is added NaH (221 mg, 9.20 mmol, 1.50 eq) at 0 °C. After stirred for 30 min, 1- bromobutane (1.01 g, 7.36 mmol, 794 mL, 1.20 eq) is added. The mixture is stirred at 25 °C for 12 hr. The mixture is quenched by water (20 mL), extracted with ethyl acetate (50 mL*2).
  • Step 2 To a solution of 1-butyl-6-nitro-indazole (350 mg, 1.60 mmol, 1.00 eq) in H2O (10.00 mL) and EtOH (30 mL) is added NH4Cl (856 mg, 16.0 mmol, 559 mL, 10.0 eq). The solution is stirred for 30 min at 80 °C. Then Fe (446.80 mg, 8.00 mmol, 5.00 eq) is added in one portion. The mixture is stirred at 80 °C for 4 hrs. The solid is removed by filtration. The filtrate is extracted with ethyl acetate (30 mL*2). The combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product 1-butylindazol-6-amine is used into the next step without further purification.
  • Step 3 To a solution of 1-butylindazol-6-amine (300 mg, 1.59 mmol, 1.00 eq) in DCM (5.00 mL) is added CDI (284 mg, 1.75 mmol, 1.10 eq). After stirred for 1 hr, the amine (2R)-2-amino-2-phenyl-ethanol (261.74 mg, 1.91 mmol, 1.20 eq) is added. The mixture is stirred at 25 °C for 5 hrs. The mixture is concentrated in reduced pressure.
  • dichloromethane (5 mL) is added triethylamine (1.34 g, 13.2 mmol, 1.83 mL, 1.50 eq) and methanesulfonyl chloride (1.21 g, 10.6 mmol, 818 mL, 1.20 eq) dropwise at 0 °C. The mixture is stirred at 25 °C for 1 hour. The reaction mixture is diluted with water (10 mL) and extracted with dichloromethane (3 mL ⁇ 3). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-cyclopropylethyl methanesulfonate.
  • Step 2 To a solution of Intermediate A11 ([(2R)-2-[(3-hydroxy-4-methoxy- phenyl)carbamoylamino]-2-phenyl-ethyl] acetate) (1.50 g, 4.36 mmol, 1.00 eq) in dimethyl formamide (20 mL) is added cesium carbonate (5.68 g, 17.42 mmol, 4.00 eq) and the product from Step 1 (1.50 eq). The mixture is stirred at 85 °C for 12 hours. The reaction mixture is poured into water (50 mL) at 0 °C, extracted with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue is purified by prep-HPLC and lyophilized to afford SM0101.
  • reaction mixture is diluted with water (20 mL) and extracted with ethyl acetate (20 mL ⁇ 2). The combined organic layers are washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by prep-HPLC, the solution of ACN and
  • Step 1 To a solution of pyrimidin-5-ylmethanol (100 mg, 908 mmol, 1.0 eq) in dichloromethane (10 mL) is added thionyl chloride (864 mg, 7.27 mmol, 527 mL, 8.0 eq) dropwise at 0 °C, then the mixture is stirred at 50 °C for 2 hours. The reaction mixture is concentrated under reduced pressure to give 5-(chloromethyl)pyrimidine (100 mg, crude) as yellow oil.
  • Step 2 To a solution of Intermediate A5 (1-(3-hydroxy-4-methoxy-phenyl)-3- [(1R)-2-hydroxy-1-phenyl-ethyl]urea) (100 mg, 331 mmol, 1.0 eq) in dimethyl formamide (5 mL) is added cesium carbonate (216 mg, 662 mmol, 2.0 eq) and 5-(chloromethyl)pyrimidine (63.8 mg, 496 mmol, 1.5 eq). The mixture is stirred at 25 °C for 12 hrs. The reaction mixture is poured into water, and then extracted with dichloromethane:isopropanol. The combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 1 To a mixture of 3-aminobenzoic acid (200 mg, 1.46 mmol, 1.00 eq) and propylphosphonic anhydride (T3P, 697 mg, 2.19 mmol, 651 mL, 1.50 eq) in acetonitrile (3 mL) is added triethylamine (295 mg, 2.92 mmol, 405 mL, 2.00 eq) , N-methylbutan-1-amine (153 mg, 1.75 mmol, 206 mL, 1.20 eq). The mixture is stirred at 25 °C for 12 hours. The reaction mixture is concentrated.
  • T3P propylphosphonic anhydride
  • Step 2 To a mixture of 3-amino-N-butyl-N-methyl-benzamide (200 mg, 970 mmol, 1.00 eq) and triethylamine (196 mg, 1.94 mmol, 269 mL, 2.00 eq) in dioxane (3 mL) is added phenyl N-[(1R)-2-[tert-butyl(dimethyl)silyl] oxy-1-phenyl-ethyl]carbamate (432 mg, 1.16 mmol, 1.20 eq). The mixture is stirred at 110 °C for 12 hours. The reaction mixture is concentrated to give a residue.
  • Step 3 To a mixture of N-butyl-3-[[(1R)-2-[tert-butyl(dimethyl)silyl]oxy-1- phenyl-ethyl]carbamoylamino]-N- methyl-benzamide (100 mg, 207 mmol, 1.00 eq) in methanol (2 mL) is added HCl solution (4 M in methanol, 2 mL). The mixture is stirred at 25 °C for 2 hours. The mixture is concentrated in vacuum. The reaction mixture is concentrated and the residue is diluted with water (20 mL). The mixture is extracted with ethyl acetate (10 mL ⁇ 2).

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